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1
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Agrawal M, Kumar Singh S, Baidya M, Kumari P. Breaking the one-site myth: the multifaceted world of proton sensing in GPCRs. FEBS J 2025. [PMID: 40418645 DOI: 10.1111/febs.70145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2025] [Revised: 05/01/2025] [Accepted: 05/18/2025] [Indexed: 05/28/2025]
Abstract
Proton-sensing GPCRs detect extracellular acidification and play a pivotal role in maintaining pH homeostasis, influencing processes such as inflammation, cancer progression, and neuropathic pain. While initially believed to rely solely on histidine protonation for activation, emerging evidence suggests that acidic triads, beyond histidine residues, are crucial for proton sensing. Variations in histidine distribution and sequence composition among these receptors point to distinct activation mechanisms within the proton-sensing GPCR family. This Viewpoint consolidates findings from previously published studies to explore the structural and molecular intricacies of proton recognition, receptor activation, and downstream signaling in proton-sensing GPCRs. By integrating insights from molecular dynamics simulations, evolutionary analysis, structural studies, and functional assays, we highlight the complex and multifaceted nature of GPCRs in proton sensing. Collectively, these studies reveal a previously unrecognized network of critical residues and activation sites, reshaping our understanding of GPCR function. Beyond structural and mechanistic insights, this compilation of findings offers new perspectives on targeting proton-sensing pathways for therapeutic intervention in various diseases.
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Affiliation(s)
- Mahek Agrawal
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India
| | - Swapnil Kumar Singh
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India
| | - Mithu Baidya
- Department of Biological Sciences and Bioengineering, Indian Institute of Technology Jammu, India
| | - Punita Kumari
- Department of Biological Sciences, Indian Institute of Science Education and Research, Bhopal, India
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2
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Mavuluri J, Dhungana Y, Jones LL, Bhatara S, Shi H, Yang X, Lim SE, Reyes N, Chi H, Yu J, Geiger TL. GPR65 Inactivation in Tumor Cells Drives Antigen-Independent CAR T-cell Resistance via Macrophage Remodeling. Cancer Discov 2025; 15:1018-1036. [PMID: 39998425 PMCID: PMC12046320 DOI: 10.1158/2159-8290.cd-24-0841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 11/28/2024] [Accepted: 02/05/2025] [Indexed: 02/26/2025]
Abstract
SIGNIFICANCE The study identifies GPR65 as an important determinant of B-cell acute lymphoblastic leukemia response to CAR T-cell therapy. Notably, GPR65 absence signals CAR T resistance. By emphasizing the therapeutic potential of targeting VEGFA or host macrophages, our study identifies routes to optimize CAR T-cell therapy outcomes in hematologic malignancies via tumor microenvironment manipulation.
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Affiliation(s)
- Jayadev Mavuluri
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Yogesh Dhungana
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Lindsay L. Jones
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Sheetal Bhatara
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Hao Shi
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Xu Yang
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Song-Eun Lim
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Noemi Reyes
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, Tennessee
| | - Hongbo Chi
- Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Jiyang Yu
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Terrence L. Geiger
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital, Memphis, Tennessee
- Department of Immunology, St. Jude Children’s Research Hospital, Memphis, Tennessee
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3
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Hurtado-Lorenzo A, Swantek JL. The landscape of new therapeutic opportunities for IBD. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2024; 101:1-83. [PMID: 39521596 DOI: 10.1016/bs.apha.2024.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
This chapter presents an overview of the emerging strategies to address the unmet needs in the management of inflammatory bowel diseases (IBD). IBD poses significant challenges, as over half of patients experience disease progression despite interventions, leading to irreversible complications, and a substantial proportion do not respond to existing therapies, such as biologics. To overcome these limitations, we describe a diverse array of novel therapeutic approaches. In the area of immune homeostasis restoration, the focus is on targeting cytokine networks, leukocyte trafficking, novel immune pathways, and cell therapies involving regulatory T cells and mesenchymal stem cells (MSC). Recognizing the critical role of impaired intestinal barrier integrity in IBD, we highlight therapies aimed at restoring barrier function and promoting mucosal healing, such as those targeting cell proliferation, tight junctions, and lipid mediators. Addressing the challenges posed by fibrosis and fistulas, we describe emerging targets for reversing fibrosis like kinase and cytokine inhibitors and nuclear receptor agonists, as well as the potential of MSC for fistulas. The restoration of a healthy gut microbiome, through strategies like fecal microbiota transplantation, rationally defined bacterial consortia, and targeted antimicrobials, is also highlighted. We also describe innovative approaches to gut-targeted drug delivery to enhance efficacy and minimize side effects. Reinforcing these advancements is the critical role of precision medicine, which emphasizes the use of multiomics analysis for the discovery of biomarkers to enable personalized IBD care. Overall, the emerging landscape of therapeutic opportunities for IBD holds great potential to surpass the therapeutic ceiling of current treatments.
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Affiliation(s)
- Andrés Hurtado-Lorenzo
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States.
| | - Jennifer L Swantek
- Translational Research & IBD Ventures, Research Department, Crohn's & Colitis Foundation, New York, NY, United States
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Dai SP, Yang CC, Chin Y, Sun WH. T cell death-associated gene 8-mediated distinct signaling pathways modulate the early and late phases of neuropathic pain. iScience 2024; 27:110955. [PMID: 39381739 PMCID: PMC11460492 DOI: 10.1016/j.isci.2024.110955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 05/01/2024] [Accepted: 09/10/2024] [Indexed: 10/10/2024] Open
Abstract
Peripheral nerve injury alters the transduction of nociceptive signaling. The coordination of neurons, glia, and immune cells results in persistent pain and inflammation. T cell death-associated gene 8 (TDAG8), located at nociceptors and immune cells, is involved in inflammatory pain and arthritis-induced pain. Here, we employed TDAG8-deficient mice, pharmacological approaches, and calcium/sodium imaging to elucidate how TDAG8-mediated signaling modulates neuron activities in a mouse model of chronic constriction injury-induced neuropathic pain. We demonstrated that TDAG8 participated alone in mechanical allodynia induced by constriction injury. (1) TDAG8-Nav1.8 signaling in small-diameter isolectin B4-positive [IB4(+)] neurons initiates mechanical allodynia; it also modulated substance P release from IB4(-) neurons to facilitate the development of early mechanical allodynia. (2) TDAG8-mediated signaling increased medium-to large-diameter IB4(-) neuron activity to maintain late mechanical allodynia; it also modulated substance P release in soma to reduce satellite glial number and Nav1.7 expression, thus attenuating chronic mechanical allodynia.
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Affiliation(s)
- Shih-Ping Dai
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Chieh Yang
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan
| | - Yin Chin
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Wei-Hsin Sun
- Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan
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5
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Li S, Melchiore F, Kantari-Mimoun C, Mouton A, Knockaert S, Philippon W, Chanrion B, Bourgeois C, Lefebvre C, Elhmouzi-Younes J, Blanc V, Ramon Olayo F, Laugel B. In silico and pharmacological evaluation of GPR65 as a cancer immunotherapy target regulating T-cell functions. Front Immunol 2024; 15:1483258. [PMID: 39483470 PMCID: PMC11525786 DOI: 10.3389/fimmu.2024.1483258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 09/30/2024] [Indexed: 11/03/2024] Open
Abstract
The success of cancer immunotherapies such as immune checkpoint inhibitors, CAR T-cells and immune cell engagers have provided clinicians with tools to bypass some of the limitations of cancer immunity. However, numerous tumour factors curtail the immune response against cancer and limit the efficiency of immuno-oncology (IO) therapies. Acidification of the extra-cellular tumour environment consecutive to aberrant cancer cell metabolism is a well-known promoter of oncogenic processes that also acts as an immune regulator. Yet, the suppressive mechanisms of low extra-cellular pH on anti-cancer immunity remain poorly understood. Recent reports have suggested that GPR65, a Gαs-coupled proton-sensing GPCR broadly expressed in the immune system, may act as an immune suppressant detrimental to anti-tumour immunity. So far, the immuno-regulatory properties of GPR65 in acidic milieux have mostly been documented in macrophages and myeloid cells. Our computational evaluation of GPR65's transcriptomic expression profile and potential as an IO target using public datasets prompted us to further investigate its functions in human T-cells. To this end, we identified and validated GPR65 small molecule inhibitors active in in vitro cellular assays and we showed that GPR65 inhibition promoted the killing capacity of antigen-specific human T-cells. Our results broaden the scope of GPR65 as an IO target by suggesting that its inhibition may enhance T-cell anti-tumour activity and provide useful pharmacological tools to further investigate the therapeutic potential of GPR65 inhibition.
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Affiliation(s)
- Shamin Li
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | - Fabien Melchiore
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | | | - Aurore Mouton
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | - Samantha Knockaert
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | - Wendy Philippon
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | - Benjamin Chanrion
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | | | - Céline Lefebvre
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | | | - Véronique Blanc
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
| | | | - Bruno Laugel
- Institut de Recherches Servier, Paris-Saclay R&D Center, Gif-sur-Yvette, France
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6
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Bouyer PG, Salameh AI, Zhou Y, Kolba TN, Boron WF. Effects of extracellular metabolic acidosis and out-of-equilibrium CO 2/HCO 3 - solutions on intracellular pH in cultured rat hippocampal neurons. Front Physiol 2024; 15:1434359. [PMID: 39444753 PMCID: PMC11496273 DOI: 10.3389/fphys.2024.1434359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Accepted: 08/28/2024] [Indexed: 10/25/2024] Open
Abstract
Metabolic acidosis (MAc)-an extracellular pH (pHo) decrease caused by a [HCO3 -]o decrease at constant [CO2]o-usually causes intracellular pH (pHi) to fall. Here we determine the extent to which the pHi decrease depends on the pHo decrease vs the concomitant [HCO3 -]o decrease. We use rapid-mixing to generate out-of-equilibrium CO2/HCO3 - solutions in which we stabilize [CO2]o and [HCO3 -]o while decreasing pHo (pure acidosis, pAc), or stabilize [CO2]o and pHo while decreasing [HCO3 -]o (pure metabolic/down, pMet↓). Using the fluorescent dye 2',7'-bis-2-carboxyethyl)-5(and-6)carboxyfluorescein (BCECF) to monitor pHi in rat hippocampal neurons in primary culture, we find that-in naïve neurons-the pHi decrease caused by MAc is virtually the sum of those caused by pAc (∼70%) + pMet↓ (∼30%). However, if we impose a first challenge (MAc1, pAc1, or pMet↓1), allow the neurons to recover, and then impose a second challenge (MAc2, pAc2, or pMet↓2), we find that pAc/pMet↓ additivity breaks down. In a twin-challenge protocol in which challenge #2 is MAc, the pHo and [HCO3 -]o decreases during challenge #1 must be coincident in order to mimic the effects of MAc1 on MAc2. Conversely, if challenge #1 is MAc, then the pHo and [HCO3 -]o decreases during challenge #2 must be coincident in order for MAc1 to produce its physiological effects during the challenge #2 period. We conclude that the history of challenge #1 (MAc1, pAc1, or pMet↓1)-presumably as detected by one or more acid-base sensors-has a major impact on the pHi response during challenge #2 (MAc2, pAc2, or pMet↓2).
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Affiliation(s)
- Patrice G. Bouyer
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
- Department of Biology, Valparaiso University, Valparaiso, IN, United States
| | - Ahlam I. Salameh
- Preclinical Sciences Division, Kent State University College of Podiatric Medicine, Independence, OH, United States
- Department of Physiology & Biophysics Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Yuehan Zhou
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
- Department of Physiology & Biophysics Case Western Reserve University School of Medicine, Cleveland, OH, United States
| | - Tiffany N. Kolba
- Department of Mathematics & Statistics, Valparaiso University, Valparaiso, IN, United States
| | - Walter F. Boron
- Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
- Department of Physiology & Biophysics Case Western Reserve University School of Medicine, Cleveland, OH, United States
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7
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Dickinson K, Yee EJ, Vigil I, Schulick RD, Zhu Y. GPCRs: emerging targets for novel T cell immune checkpoint therapy. Cancer Immunol Immunother 2024; 73:253. [PMID: 39358616 PMCID: PMC11447192 DOI: 10.1007/s00262-024-03801-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/05/2024] [Indexed: 10/04/2024]
Abstract
Although immune checkpoint blockade (ICB) has become the mainstay of treatment for advanced solid organ malignancies, success in revitalizing the host anticancer immune response remains limited. G-protein coupled receptors (GPCRs) are a broad family of cell-surface proteins that have been regarded as main players in regulating the immune system, namely by mediating the activity of T lymphocytes. Among the most novel immunoregulatory GPCRs include GPR171, lysophosphatidic acid receptors (LPARs), GPR68, cannabinoid receptor 2 (CB2), and prostaglandin E receptors, many of which have shown promise in mediating antitumor response via activation of cytotoxic T cells, inhibiting immunosuppressive lymphocytes, and facilitating immune cell infiltration within the tumor microenvironment across multiple types of cancers. This paper reviews our current understanding of some of the most novel GPCRs-their expression patterns, evolving roles within the immune system and cancer, potential therapeutic applications, and perspective for future investigation.
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Affiliation(s)
- Kaitlyn Dickinson
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Elliott J Yee
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Isaac Vigil
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Richard D Schulick
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Yuwen Zhu
- Department of Surgery, Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
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8
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Justus CR, Marie MA, Sanderlin EJ, Yang LV. The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer. Genes (Basel) 2024; 15:1151. [PMID: 39336742 PMCID: PMC11431078 DOI: 10.3390/genes15091151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Revised: 08/27/2024] [Accepted: 08/27/2024] [Indexed: 09/30/2024] Open
Abstract
The precise regulation of pH homeostasis is crucial for normal physiology. However, in tissue microenvironments, it can be impacted by pathological conditions such as inflammation and cancer. Due to the overproduction and accumulation of acids (protons), the extracellular pH is characteristically more acidic in inflamed tissues and tumors in comparison to normal tissues. A family of proton-sensing G-protein-coupled receptors (GPCRs) has been identified as molecular sensors for cells responding to acidic tissue microenvironments. Herein, we review the current research progress pertaining to these proton-sensing GPCRs, including GPR4, GPR65 (TDAG8), and GPR68 (OGR1), in inflammation and cancer. Growing evidence suggests that GPR4 and GPR68 are mainly pro-inflammatory, whereas GPR65 is primarily anti-inflammatory, in various inflammatory disorders. Both anti- and pro-tumorigenic effects have been reported for this family of receptors. Moreover, antagonists and agonists targeting proton-sensing GPCRs have been developed and evaluated in preclinical models. Further research is warranted to better understand the roles of these proton-sensing GPCRs in pathophysiology and is required in order to exploit them as potential therapeutic targets for disease treatment.
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Affiliation(s)
- Calvin R Justus
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Mona A Marie
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Edward J Sanderlin
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Li V Yang
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
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9
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Gonzalez-Llerena JL, Espinosa-Rodriguez BA, Treviño-Almaguer D, Mendez-Lopez LF, Carranza-Rosales P, Gonzalez-Barranco P, Guzman-Delgado NE, Romo-Mancillas A, Balderas-Renteria I. Cordycepin Triphosphate as a Potential Modulator of Cellular Plasticity in Cancer via cAMP-Dependent Pathways: An In Silico Approach. Int J Mol Sci 2024; 25:5692. [PMID: 38891880 PMCID: PMC11171877 DOI: 10.3390/ijms25115692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 05/14/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Cordycepin, or 3'-deoxyadenosine, is an adenosine analog with a broad spectrum of biological activity. The key structural difference between cordycepin and adenosine lies in the absence of a hydroxyl group at the 3' position of the ribose ring. Upon administration, cordycepin can undergo an enzymatic transformation in specific tissues, forming cordycepin triphosphate. In this study, we conducted a comprehensive analysis of the structural features of cordycepin and its derivatives, contrasting them with endogenous purine-based metabolites using chemoinformatics and bioinformatics tools in addition to molecular dynamics simulations. We tested the hypothesis that cordycepin triphosphate could bind to the active site of the adenylate cyclase enzyme. The outcomes of our molecular dynamics simulations revealed scores that are comparable to, and superior to, those of adenosine triphosphate (ATP), the endogenous ligand. This interaction could reduce the production of cyclic adenosine monophosphate (cAMP) by acting as a pseudo-ATP that lacks a hydroxyl group at the 3' position, essential to carry out nucleotide cyclization. We discuss the implications in the context of the plasticity of cancer and other cells within the tumor microenvironment, such as cancer-associated fibroblast, endothelial, and immune cells. This interaction could awaken antitumor immunity by preventing phenotypic changes in the immune cells driven by sustained cAMP signaling. The last could be an unreported molecular mechanism that helps to explain more details about cordycepin's mechanism of action.
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Affiliation(s)
- Jose Luis Gonzalez-Llerena
- Laboratory of Molecular Pharmacology and Biological Models, School of Chemistry, Autonomous University of Nuevo Leon, San Nicolas de los Garza 66451, Mexico; (J.L.G.-L.); (B.A.E.-R.); (D.T.-A.); (P.G.-B.)
- Center for Research on Nutrition and Public Health, School of Public Health and Nutrition, Autonomous University of Nuevo Leon, Monterrey 66460, Mexico;
| | - Bryan Alejandro Espinosa-Rodriguez
- Laboratory of Molecular Pharmacology and Biological Models, School of Chemistry, Autonomous University of Nuevo Leon, San Nicolas de los Garza 66451, Mexico; (J.L.G.-L.); (B.A.E.-R.); (D.T.-A.); (P.G.-B.)
| | - Daniela Treviño-Almaguer
- Laboratory of Molecular Pharmacology and Biological Models, School of Chemistry, Autonomous University of Nuevo Leon, San Nicolas de los Garza 66451, Mexico; (J.L.G.-L.); (B.A.E.-R.); (D.T.-A.); (P.G.-B.)
| | - Luis Fernando Mendez-Lopez
- Center for Research on Nutrition and Public Health, School of Public Health and Nutrition, Autonomous University of Nuevo Leon, Monterrey 66460, Mexico;
| | - Pilar Carranza-Rosales
- Laboratory of Cell Biology, Northeast Biomedical Research Center, Mexican Social Security Institute, Monterrey 64720, Mexico;
| | - Patricia Gonzalez-Barranco
- Laboratory of Molecular Pharmacology and Biological Models, School of Chemistry, Autonomous University of Nuevo Leon, San Nicolas de los Garza 66451, Mexico; (J.L.G.-L.); (B.A.E.-R.); (D.T.-A.); (P.G.-B.)
| | - Nancy Elena Guzman-Delgado
- Health Research Division, High Specialty Medical Unit, Cardiology Hospital N. 34. Mexican Social Security Institute, Monterrey 64360, Mexico;
| | - Antonio Romo-Mancillas
- Computer Aided Drug Design and Synthesis Group, School of Chemistry, Autonomous University of Queretaro, Queretaro 76010, Mexico
| | - Isaias Balderas-Renteria
- Laboratory of Molecular Pharmacology and Biological Models, School of Chemistry, Autonomous University of Nuevo Leon, San Nicolas de los Garza 66451, Mexico; (J.L.G.-L.); (B.A.E.-R.); (D.T.-A.); (P.G.-B.)
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10
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Xu C, Wang Y, Ni H, Yao M, Cheng L, Lin X. The role of orphan G protein-coupled receptors in pain. Heliyon 2024; 10:e28818. [PMID: 38590871 PMCID: PMC11000026 DOI: 10.1016/j.heliyon.2024.e28818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/10/2024] Open
Abstract
G protein-coupled receptors (GPCRs), which form the largest family of membrane protein receptors in humans, are highly complex signaling systems with intricate structures and dynamic conformations and locations. Among these receptors, a specific subset is referred to as orphan GPCRs (oGPCRs) and has garnered significant interest in pain research due to their role in both central and peripheral nervous system function. The diversity of GPCR functions is attributed to multiple factors, including allosteric modulators, signaling bias, oligomerization, constitutive signaling, and compartmentalized signaling. This review primarily focuses on the recent advances in oGPCR research on pain mechanisms, discussing the role of specific oGPCRs including GPR34, GPR37, GPR65, GPR83, GPR84, GPR85, GPR132, GPR151, GPR160, GPR171, GPR177, and GPR183. The orphan receptors among these receptors associated with central nervous system diseases are also briefly described. Understanding the functions of these oGPCRs can contribute not only to a deeper understanding of pain mechanisms but also offer a reference for discovering new targets for pain treatment.
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Affiliation(s)
- Chengfei Xu
- Department of Anesthesiology, The Third People's Hospital of Bengbu, Bengbu, 233000, PR China
| | - Yahui Wang
- Department of Anesthesiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, PR China
| | - Huadong Ni
- Department of Anesthesiology and Pain Research Center, Affiliated Hospital of Jiaxing University, Jiaxing, 314000, PR China
| | - Ming Yao
- Department of Anesthesiology and Pain Research Center, Affiliated Hospital of Jiaxing University, Jiaxing, 314000, PR China
| | - Liang Cheng
- Department of Anesthesiology, The Third People's Hospital of Bengbu, Bengbu, 233000, PR China
| | - Xuewu Lin
- Department of Anesthesiology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, 233000, PR China
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11
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Otsugu M, Mine A, Uchida I, Miyake Y, Tachihara R, Fujiwara K, Ichimura A, Sato K, Tomura H. Low pH modulates lipopolysaccharide-induced tumor necrosis factor-alpha expression and macropinocytotic activity in RAW264.7 cells. J Recept Signal Transduct Res 2024; 44:63-71. [PMID: 39175331 DOI: 10.1080/10799893.2024.2395310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 08/12/2024] [Accepted: 08/17/2024] [Indexed: 08/24/2024]
Abstract
Inflammation triggers various types of diseases that need to be addressed. Macrophages play important roles in the inflammatory responses. As atherosclerosis progresses, macrophages transform into foam cells. Extracellular acidification is observed at and around bacterial infection and atherosclerotic sites. However, the effects of acidification on the inflammatory response of macrophages and the progression of atherosclerosis have not been fully understood. This study investigates the impact of extracellular acidification on lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-α) expression and macropinocytotic activity in RAW264.7 cells. TNF-α expression is measured by real-time polymerase chain reaction (relative value to glyceraldehyde-3-phosphate dehydrogenase expression). Macropinocytotic activity is measured by neutral red uptake (absorbance at 540 nm). Results show that TNF-α expression increased with decreasing extracellular pH in both un-foamed and foamed cells. Macropinocytotic activity was upregulated at pH 6.8 in un-foamed cells, but downregulated in foamed cells stimulated at low pH. Proton-sensing G protein-coupled receptors (GPCRs) were involved in the expression of TNF-α and in the macropinocytotic activity of foamed cells. In conclusion, this study reveals that extracellular acidification differently affect various inflammatory responses such as LPS-induced TNF-α expression and macropinocytotic activity of RAW264.7 cells and different proton-sensing GPCRs are involved in the different inflammatory responses.
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Affiliation(s)
- Miku Otsugu
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Ayumi Mine
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Izumi Uchida
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Yuta Miyake
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Ryo Tachihara
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Kurumi Fujiwara
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Ayako Ichimura
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
| | - Koichi Sato
- Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Hideaki Tomura
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, Japan
- Institute of Endocrinology, Meiji University, Kawasaki, Japan
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Hausmann M, Seuwen K, de Vallière C, Busch M, Ruiz PA, Rogler G. Role of pH-sensing receptors in colitis. Pflugers Arch 2024; 476:611-622. [PMID: 38514581 PMCID: PMC11006753 DOI: 10.1007/s00424-024-02943-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 03/06/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024]
Abstract
Low pH in the gut is associated with severe inflammation, fibrosis, and colorectal cancer (CRC) and is a hallmark of active inflammatory bowel disease (IBD). Subsequently, pH-sensing mechanisms are of interest for the understanding of IBD pathophysiology. Tissue hypoxia and acidosis-two contributing factors to disease pathophysiology-are linked to IBD, and understanding their interplay is highly relevant for the development of new therapeutic options. One member of the proton-sensing G protein-coupled receptor (GPCR) family, GPR65 (T-cell death-associated gene 8, TDAG8), was identified as a susceptibility gene for IBD in a large genome-wide association study. In response to acidic extracellular pH, GPR65 induces an anti-inflammatory response, whereas the two other proton-sensing receptors, GPR4 and GPR68 (ovarian cancer G protein-coupled receptor 1, OGR1), mediate pro-inflammatory responses. Here, we review the current knowledge on the role of these proton-sensing receptors in IBD and IBD-associated fibrosis and cancer, as well as colitis-associated cancer (CAC). We also describe emerging small molecule modulators of these receptors as therapeutic opportunities for the treatment of IBD.
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Affiliation(s)
- Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland.
| | - Klaus Seuwen
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Moana Busch
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091, Zurich, CH, Switzerland
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13
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Caratis F, Opiełka M, Hausmann M, Velasco-Estevez M, Rojek B, de Vallière C, Seuwen K, Rogler G, Karaszewski B, Rutkowska A. The proton-sensing receptors TDAG8 and GPR4 are differentially expressed in human and mouse oligodendrocytes: Exploring their role in neuroinflammation and multiple sclerosis. PLoS One 2024; 19:e0283060. [PMID: 38527054 PMCID: PMC10962805 DOI: 10.1371/journal.pone.0283060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 02/13/2024] [Indexed: 03/27/2024] Open
Abstract
Acidosis is one of the hallmarks of demyelinating central nervous system (CNS) lesions in multiple sclerosis (MS). The response to acidic pH is primarily mediated by a family of G protein-coupled proton-sensing receptors: OGR1, GPR4 and TDAG8. These receptors are inactive at alkaline pH, reaching maximal activation at acidic pH. Genome-wide association studies have identified a locus within the TDAG8 gene associated with several autoimmune diseases, including MS. Accordingly, we here found that expression of TDAG8, as opposed to GPR4 or OGR1, is upregulated in MS plaques. This led us to investigate the expression of TDAG8 in oligodendrocytes using mouse and human in vitro and in vivo models. We observed significant upregulation of TDAG8 in human MO3.13 oligodendrocytes during maturation and in response to acidic conditions. However, its deficiency did not impact normal myelination in the mouse CNS, and its expression remained unaltered under demyelinating conditions in mouse organotypic cerebellar slices. Notably, our data revealed no expression of TDAG8 in primary mouse oligodendrocyte progenitor cells (OPCs), in contrast to its expression in primary human OPCs. Our investigations have revealed substantial species differences in the expression of proton-sensing receptors in oligodendrocytes, highlighting the limitations of the employed experimental models in fully elucidating the role of TDAG8 in myelination and oligodendrocyte biology. Consequently, the study does not furnish robust evidence for the role of TDAG8 in such processes. Nonetheless, our findings tentatively point towards a potential association between TDAG8 and myelination processes in humans, hinting at a potential link between TDAG8 and the pathophysiology of MS and warrants further research.
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Affiliation(s)
- Fionä Caratis
- Brain Diseases Centre, Medical University of Gdansk, Gdansk, Poland
- Department of Anatomy and Neurobiology, Medical University of Gdansk, Gdansk, Poland
| | - Mikołaj Opiełka
- Brain Diseases Centre, Medical University of Gdansk, Gdansk, Poland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Maria Velasco-Estevez
- H12O-CNIO Hematological Malignancies Group, Clinical Research Unit, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain
| | - Bartłomiej Rojek
- Department of Adult Neurology, Medical University of Gdansk & University Clinical Centre, Gdansk, Poland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Klaus Seuwen
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
| | - Bartosz Karaszewski
- Brain Diseases Centre, Medical University of Gdansk, Gdansk, Poland
- Department of Adult Neurology, Medical University of Gdansk & University Clinical Centre, Gdansk, Poland
| | - Aleksandra Rutkowska
- Brain Diseases Centre, Medical University of Gdansk, Gdansk, Poland
- Department of Anatomy and Neurobiology, Medical University of Gdansk, Gdansk, Poland
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14
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Qi J, Liu S, Zhang Z. What role does GPR65 play in the progression of osteosarcoma? Its mechanism and clinical significance. Cancer Cell Int 2024; 24:31. [PMID: 38218960 PMCID: PMC10788037 DOI: 10.1186/s12935-024-03216-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/03/2024] [Indexed: 01/15/2024] Open
Abstract
BACKGROUND GPR65 is a pH-sensing G-protein-coupled receptor that acts as a key innate immune checkpoint in the human tumor microenvironment, inhibiting the release of inflammatory factors and inducing significant upregulation of tissue repair genes. However, the expression pattern and function of GPR65 in osteosarcoma (OS) remain unclear. The purpose of this study was to investigate and elucidate the role of GPR65 in the microenvironment, proliferation and migration of OS. METHODS Retrospective RNA-seq data analysis was conducted in a cohort of 97 patients with OS data in the TAEGET database. In addition, single-cell sequencing data from six surgical specimens of human OS patients was used to analyze the molecular evolution process during OS genesis. Tissues chips and bioinformatics results were used to verify GPR65 expression level in OS. MTT, colony formation, EdU assay, wound healing, transwell assay and F-actin assay were utilized to analyze cell proliferation and invasion of OS cancer cells. RNA-seq was used to explore the potential mechanism of GPR65's role in OS. RESULTS GPR65 expression was significantly low in OS, and subgroup analysis found that younger OS patients, OS patients in metastatic status, and overall survival and progression free survival OS patients had lower GPR65 expression. From ScRNA-seq data of GSE162454, we found the expression of GPR65 is significantly positively correlated with CD4 + T cells CD8 + T cells and OS related macrophage infiltration. Verification experiment found that silencing the expression of GPR65 in osteosarcoma cells U2OS and HOS could promote the proliferation and invasion process, RNA-seq results showed that the role of GPR65 in OS cells was related to immune system, metabolism and signal transduction. CONCLUSION The low expression of GPR65 in OS leads to high metastasis rate and poor prognosis in OS patients. The suppression of immune escape and inhibition of proliferation may be a key pathway for GPR65 to participate in the progression of OS. The current study strengthens the role of GPR65 in OS development and provides a potential biomarker for the prognosis of OS patients.
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Affiliation(s)
- Jin Qi
- Department of Orthopedics, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui Province, China
| | - Sihang Liu
- Department of Orthopedics, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui Province, China
| | - Zhirui Zhang
- Department of Pharmacy, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, 241001, Anhui Province, China.
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15
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Marie MA, Sanderlin EJ, Hoffman AP, Cashwell KD, Satturwar S, Hong H, Sun Y, Yang LV. GPR4 Knockout Attenuates Intestinal Inflammation and Forestalls the Development of Colitis-Associated Colorectal Cancer in Murine Models. Cancers (Basel) 2023; 15:4974. [PMID: 37894341 PMCID: PMC10605520 DOI: 10.3390/cancers15204974] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/09/2023] [Accepted: 10/12/2023] [Indexed: 10/29/2023] Open
Abstract
GPR4 is a proton-sensing G protein-coupled receptor highly expressed in vascular endothelial cells and has been shown to potentiate intestinal inflammation in murine colitis models. Herein, we evaluated the proinflammatory role of GPR4 in the development of colitis-associated colorectal cancer (CAC) using the dextran sulfate sodium (DSS) and azoxymethane (AOM) mouse models in wild-type and GPR4 knockout mice. We found that GPR4 contributed to chronic intestinal inflammation and heightened DSS/AOM-induced intestinal tumor burden. Tumor blood vessel density was markedly reduced in mice deficient in GPR4, which correlated with increased tumor necrosis and reduced tumor cell proliferation. These data demonstrate that GPR4 ablation alleviates intestinal inflammation and reduces tumor angiogenesis, development, and progression in the AOM/DSS mouse model.
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Affiliation(s)
- Mona A. Marie
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (M.A.M.)
| | - Edward J. Sanderlin
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (M.A.M.)
| | - Alexander P. Hoffman
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (M.A.M.)
| | - Kylie D. Cashwell
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (M.A.M.)
| | - Swati Satturwar
- Department of Pathology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Heng Hong
- Department of Pathology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
- Department of Pathology, Wake Forest University, Winston-Salem, NC 27157, USA
| | - Ying Sun
- Department of Pathology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA
| | - Li V. Yang
- Department of Internal Medicine, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA; (M.A.M.)
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16
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Perren L, Busch M, Schuler C, Ruiz PA, Foti F, Weibel N, de Vallière C, Morsy Y, Seuwen K, Hausmann M, Rogler G. OGR1 (GPR68) and TDAG8 (GPR65) Have Antagonistic Effects in Models of Colonic Inflammation. Int J Mol Sci 2023; 24:14855. [PMID: 37834303 PMCID: PMC10573511 DOI: 10.3390/ijms241914855] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/29/2023] [Accepted: 09/29/2023] [Indexed: 10/15/2023] Open
Abstract
G-protein-coupled receptors (GPRs), including pro-inflammatory ovarian cancer GPR1 (OGR1/GPR68) and anti-inflammatory T cell death-associated gene 8 (TDAG8/GPR65), are involved in pH sensing and linked to inflammatory bowel disease (IBD). OGR1 and TDAG8 show opposite effects. To determine which effect is predominant or physiologically more relevant, we deleted both receptors in models of intestinal inflammation. Combined Ogr1 and Tdag8 deficiency was assessed in spontaneous and acute murine colitis models. Disease severity was assessed using clinical scores. Colon samples were analyzed using quantitative polymerase chain reaction (qPCR) and flow cytometry (FACS). In acute colitis, Ogr1-deficient mice showed significantly decreased clinical scores compared with wildtype (WT) mice, while Tdag8-deficient mice and double knockout (KO) mice presented similar scores to WT. In Il-10-spontaneous colitis, Ogr1-deficient mice presented significantly decreased, and Tdag8-deficient mice had increased inflammation. In the Il10-/- × Ogr1-/- × Tdag8-/- triple KO mice, inflammation was significantly decreased compared with Tdag8-/-. Absence of Ogr1 reduced pro-inflammatory cytokines in Tdag8-deficient mice. Tdag8-/- had significantly more IFNγ+ T-lymphocytes and IL-23 T-helper cells in the colon compared with WT. The absence of OGR1 significantly alleviates the intestinal damage mediated by the lack of functional TDAG8. Both OGR1 and TDAG8 represent potential new targets for therapeutic intervention.
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17
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Mao J, Feng Y, Zheng Y, Gao Y, Zhang L, Sun X, Wu Y, Zhu X, Ma F. GPR65 inhibits human trophoblast cell adhesion through upregulation of MYLK and downregulation of fibronectin via cAMP-ERK signaling in a low pH environment. Cell Commun Signal 2023; 21:238. [PMID: 37723567 PMCID: PMC10506227 DOI: 10.1186/s12964-023-01249-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/28/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND Extravillous trophoblasts (EVTs) are essential cells during the formation of the placenta, with the major function of invading the maternal decidua, anchoring the developing placenta to the uterus, remodeling uterine arteries, and regulating immune responses to prevent rejection. During early pregnancy, the decidua undergoes a hypoxic and acidic microenvironment, which has been shown to participate in tumor cell migration, invasion, growth, and angiogenesis. Nevertheless, the mechanisms by which EVTs sense and respond to the acidic microenvironment, thereby executing their functions, remain poorly understood. METHODS The effects of G protein-coupled receptor 65 (GPR65) on cell adhesion and other cellular functions were tested using JAR spheroids, mouse blastocysts, and HTR-8/SVneo cells. Specifically, we employed HTR-8/SVneo cells for gene overexpression and silencing to investigate the underlying mechanism of GPR65's impact on trophoblast cell function under acidic conditions. Additionally, villus tissue samples obtained from early pregnancy loss patients were utilized to explore the potential association between GPR65 and its related signaling pathway molecules with the disease. RESULTS This study identified GPR65 expression widely in trophoblasts, with the highest level in EVTs. Importantly, optimal GPR65 levels are required for maintaining normal adhesion, migration, and invasion, whereas overexpression of GPR65 inhibits these functions by activating the cAMP-ERK signaling pathway, upregulating myosin light chain kinase (MYLK) and MYLK3 expression, and subsequently downregulating fibronectin. Consistently, elevated expression of GPR65, MYLK, and MYLK3 is observed in patients suffering from early pregnancy loss. CONCLUSIONS This work offers insights into the suppressive effects of GPR65 on EVT function under acidic conditions and highlights a putative target for therapeutic intervention in early pregnancy complications. Video Abstract.
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Affiliation(s)
- Jia Mao
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, Sichuan, China
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Ying Feng
- Department of Histology, Embryology and Neurobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yayun Zheng
- Department of Histology, Embryology and Neurobiology, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yaqiu Gao
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, Sichuan, China
| | - Linyu Zhang
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xinrui Sun
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Yilun Wu
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xiaofeng Zhu
- Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, Sichuan, China.
| | - Fang Ma
- Center for Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
- Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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18
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Hung CH, Chin Y, Fong YO, Lee CH, Han DS, Lin JH, Sun WH, Chen CC. Acidosis-related pain and its receptors as targets for chronic pain. Pharmacol Ther 2023; 247:108444. [PMID: 37210007 DOI: 10.1016/j.pharmthera.2023.108444] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/24/2023] [Accepted: 05/15/2023] [Indexed: 05/22/2023]
Abstract
Sensing acidosis is an important somatosensory function in responses to ischemia, inflammation, and metabolic alteration. Accumulating evidence has shown that acidosis is an effective factor for pain induction and that many intractable chronic pain diseases are associated with acidosis signaling. Various receptors have been known to detect extracellular acidosis and all express in the somatosensory neurons, such as acid sensing ion channels (ASIC), transient receptor potential (TRP) channels and proton-sensing G-protein coupled receptors. In addition to sense noxious acidic stimulation, these proton-sensing receptors also play a vital role in pain processing. For example, ASICs and TRPs are involved in not only nociceptive activation but also anti-nociceptive effects as well as some other non-nociceptive pathways. Herein, we review recent progress in probing the roles of proton-sensing receptors in preclinical pain research and their clinical relevance. We also propose a new concept of sngception to address the specific somatosensory function of acid sensation. This review aims to connect these acid-sensing receptors with basic pain research and clinical pain diseases, thus helping with better understanding the acid-related pain pathogenesis and their potential therapeutic roles via the mechanism of acid-mediated antinociception.
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Affiliation(s)
- Chih-Hsien Hung
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yin Chin
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yi-On Fong
- Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Cheng-Han Lee
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan
| | - Der-Shen Han
- Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital, Bei-Hu Branch, Taipei, Taiwan
| | - Jiann-Her Lin
- Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei, Taiwan
| | - Wei-Hsin Sun
- Department of Life Science & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chih-Cheng Chen
- Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan; Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan.
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19
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Deai M, Oya R, Saso N, Tanaka A, Uchida I, Miyake Y, Tachihara R, Otsugu M, Mine A, Sato K, Tomura H. Ethylenediaminetetraacetic acid (EDTA) enhances cAMP production in human TDAG8-expressing cells. Biochem Biophys Res Commun 2022; 626:15-20. [PMID: 35964552 DOI: 10.1016/j.bbrc.2022.07.110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 11/02/2022]
Abstract
Ethylenediaminetetraacetic acid (EDTA) is a chelating agent that binds tightly to metal ions. We found that cAMP response element (CRE)-driven promoter activity by protons was enhanced by EDTA in human T-cell death-associated gene 8 (TDAG8)-overexpressed HEK293T cells. The enhancing action by EDTA was also detected by proton-induced cAMP production that is located upstream from the CRE-driven promoter activity even at physiological proton concentration pH7.4. The proton-induced CRE-driven promoter activity was not enhanced by other chelating agents, ethylene glycol tetraacetic acid (EGTA) and sodium citrate. The enhanced CRE-driven promoter activity by EDTA was not attenuated by increasing the extracellular calcium ion concentration. These results indicate that the EDTA-enhancing action may not be due to its chelating action but might rather be another EDTA-specific effect. Enhanced cAMP production by EDTA was also detected in a human leukemia cell line HL-60, in which TDAG8 and OGR1 (ovarian cancer G-protein-coupled receptor 1) were endogenously expressed, suggesting that the medical use of EDTA would influence the physiological and pathophysiological functions of hematopoietic cells.
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Affiliation(s)
- Masahito Deai
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Rin Oya
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Naosi Saso
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Asahi Tanaka
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Izumi Uchida
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Yuta Miyake
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Ryo Tachihara
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Miku Otsugu
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Ayumi Mine
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Koichi Sato
- Laboratory of Signal Transduction, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512, Japan
| | - Hideaki Tomura
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan; Institute of Endocrinology, Meiji University, Kawasaki, 214-8571, Japan.
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20
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Zha XM, Xiong ZG, Simon RP. pH and proton-sensitive receptors in brain ischemia. J Cereb Blood Flow Metab 2022; 42:1349-1363. [PMID: 35301897 PMCID: PMC9274858 DOI: 10.1177/0271678x221089074] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/11/2022] [Accepted: 02/28/2022] [Indexed: 01/01/2023]
Abstract
Extracellular proton concentration is at 40 nM when pH is 7.4. In disease conditions such as brain ischemia, proton concentration can reach µM range. To respond to this increase in extracellular proton concentration, the mammalian brain expresses at least three classes of proton receptors. Acid-sensing ion channels (ASICs) are the main neuronal cationic proton receptor. The proton-activated chloride channel (PAC), which is also known as (aka) acid-sensitive outwardly rectifying anion channel (ASOR; TMEM206), mediates acid-induced chloride currents. Besides proton-activated channels, GPR4, GPR65 (aka TDAG8, T-cell death-associated gene 8), and GPR68 (aka OGR1, ovarian cancer G protein-coupled receptor 1) function as proton-sensitive G protein-coupled receptors (GPCRs). Though earlier studies on these GPCRs mainly focus on peripheral cells, we and others have recently provided evidence for their functional importance in brain injury. Specifically, GPR4 shows strong expression in brain endothelium, GPR65 is present in a fraction of microglia, while GPR68 exhibits predominant expression in brain neurons. Here, to get a better view of brain acid signaling and its contribution to ischemic injury, we will review the recent findings regarding the differential contribution of proton-sensitive GPCRs to cerebrovascular function, neuroinflammation, and neuronal injury following acidosis and brain ischemia.
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Affiliation(s)
- Xiang-ming Zha
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Zhi-Gang Xiong
- Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, USA
| | - Roger P Simon
- Department of Neurobiology, Morehouse School of Medicine, Atlanta, GA, USA
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21
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Lin R, Wu W, Chen H, Gao H, Wu X, Li G, He Q, Lu H, Sun M, Liu Z. GPR65 promotes intestinal mucosal Th1 and Th17 cell differentiation and gut inflammation through downregulating NUAK2. Clin Transl Med 2022; 12:e771. [PMID: 35343079 PMCID: PMC8958354 DOI: 10.1002/ctm2.771] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 02/27/2022] [Accepted: 03/02/2022] [Indexed: 01/15/2023] Open
Abstract
G protein-coupled receptor 65 (GPR65), a susceptibility gene for inflammatory bowel diseases (IBD), has been identified to promote Th17 cell pathogenicity and induce T cell apoptosis. However, the potential role of GPR65 in modulating CD4+ T cell immune responses in the pathogenesis of IBD stills not entirely understood. Here, we displayed that GPR65 expression was increased in inflamed intestinal mucosa of IBD patients and positively associated with disease activity. It was expressed in CD4+ T cells and robustly upregulated through the TNF-α-caspase 3/8 signalling pathway. Ectopic expression of GPR65 significantly promoted the differentiation of peripheral blood (PB) CD4+ T cells from IBD patients and HC to Th1 and Th17 cells in vitro. Importantly, conditional knockout of Gpr65 in CD4+ T cells ameliorated trinitrobenzene sulfonic acid (TNBS)-induced acute murine colitis and a chronic colitis in Rag1-/- mice reconstituted with CD45RBhigh CD4+ T cells in vivo, characterised by attenuated Th1 and Th17 cell immune response in colon mucosa and decreased infiltration of CD4+ T cells, neutrophils and macrophages. RNA-seq analysis of Gpr65ΔCD4 and Gpr65flx/flx CD4+ T cells revealed that NUAK family kinase 2 (Nuak2) acts as a functional target of Gpr65 to restrict Th1 and Th17 cell immune response. Mechanistically, GPR65 deficiency promoted NUAK2 expression via the cAMP-PKA-C-Raf-ERK1/2-LKB1-mediated signalling pathway. Consistently, silencing of Nuak2 facilitated the differentiation of Gpr65ΔCD4 and Gpr65flx/flx CD4+ T cells into Th1 and Th17 cells. Therefore, our data point out that GPR65 promotes Th1 and Th17 cell immune response and intestinal mucosal inflammation by suppressing NUAK2 expression, and that targeting GPR65 and NUAK2 in CD4+ T cells may represent a novel therapeutic approach for IBD.
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Affiliation(s)
- Ritian Lin
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Wei Wu
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Huimin Chen
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Han Gao
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Xiaohan Wu
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Gengfeng Li
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Qiong He
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Huiying Lu
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Mingming Sun
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease ResearchThe Shanghai Tenth People's HospitalTongji University of School MedicineShanghaiChina
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22
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IBD-associated G protein-coupled receptor 65 variant compromises signalling and impairs key functions involved in inflammation. Cell Signal 2022; 93:110294. [PMID: 35218908 PMCID: PMC9536022 DOI: 10.1016/j.cellsig.2022.110294] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 02/06/2022] [Accepted: 02/21/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Inflammatory bowel diseases (IBD) result in chronic inflammation of the gastrointestinal tract. Genetic studies have shown that the GPR65 gene, as well as its missense coding variant, GPR65*Ile231Leu, is associated with IBD. We aimed to define the signalling and biological pathways downstream of GPR65 activation and evaluate the impact of GPR65*231Leu on these. METHODS We used HEK 293 cells stably expressing GPR65 and deficient for either Gαs, Gαq/11 or Gα12/13, to define GPR65 signalling pathways, IBD patient biopsies and a panel of human tissues, primary immune cells and cell lines to determine biologic context, and genetic modulation of human THP-1-derived macrophages to examine the impact of GPR65 in bacterial phagocytosis and NLRP3 inflammasome activation. RESULTS We confirmed that GPR65 signals via the Gαs pathway, leading to cAMP accumulation. GPR65 can also signal via the Gα12/13 pathway leading to formation of stress fibers, actin remodeling and RhoA activation; all impaired by the IBD-associated GPR65*231Leu allele. Gene expression profiling revealed greater expression of GPR65 in biopsies from inflamed compared to non-inflamed tissues from IBD patients or control individuals, potentially explained by infiltration of inflammatory immune cells. Decreased GPR65 expression in THP-1-derived macrophages leads to impaired bacterial phagocytosis, increased NLRP3 inflammasome activation and IL-1β secretion in response to an inflammatory stimulus. CONCLUSIONS We demonstrate that GPR65 exerts its effects through Gαs- and Gα12/13-mediated pathways, that the IBD-associated GPR65*231Leu allele has compromised interactions with Gα12/13 and that KD of GPR65 leads to impaired bacterial phagocytosis and increased inflammatory signalling via the NLRP3 inflammasome. This work identifies a target for development of small molecule therapies.
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23
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Jang KB, You MJ, Yang B, Rim C, Kim HJ, Kwon MS. Persistent Acidic Environment Induces Impaired Phagocytosis via ERK in Microglia. Neurochem Res 2022; 47:1341-1353. [PMID: 35103911 DOI: 10.1007/s11064-022-03533-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/23/2021] [Accepted: 01/17/2022] [Indexed: 12/28/2022]
Abstract
Acidic environment evoked by stroke, traumatic brain injury, and Alzheimer's disease may change the functional properties of microglia. Nevertheless, the underlying mechanisms of functional changes in microglia remain unclear. In this study, we found that acidic stimuli (pH 6.8) increased rapidly interleukin (IL)-1β and IL-6 mRNA levels and subsequently reduced IL-10, transforming growth factor (TGF)-β1, Cx3cr1, and P2ry12 as the exposure time to acidic environment increase in BV2 cells. In addition, persistent acidic environment (pH 6.8 for 6 h) induced impaired phagocytic function in BV2 cells. Short-term acidic exposure (pH 6.8 for 30 min) increased cyclic AMP (cAMP) and phospho-protein kinase A (PKA) but inhibited phospho-extracellular signal-regulated kinase (p-ERK). However, under persistent acidic environment (pH 6.8 for 6 h), cyclic AMP and PKA were normalized and p-ERK was increased with TDAG8 (T cell death associated gene 8; GPR65) reduction. FR 180,204, an ERK inhibitor, rescued the persistent acidic environment-induced functional changes in BV2 cells and its effect was recapitulated in primary neonatal microglia. Thus, we propose that ERK targeting may be an alternative strategy to restore microglial dysfunction in the central nervous system (CNS) acidic environment in various neurological disorders.
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Affiliation(s)
- Kyu-Beom Jang
- Department of Pharmacology, Research Institute for Basic Medical Science, School of Medicine, CHA BIO COMPLEX, CHA University, 335 Pangyo, Bundang-gu, Gyeonggi-do, Seongnam-si, 13488, Republic of Korea
| | - Min-Jung You
- Department of Pharmacology, Research Institute for Basic Medical Science, School of Medicine, CHA BIO COMPLEX, CHA University, 335 Pangyo, Bundang-gu, Gyeonggi-do, Seongnam-si, 13488, Republic of Korea
| | - Bohyun Yang
- Department of Pharmacology, Research Institute for Basic Medical Science, School of Medicine, CHA BIO COMPLEX, CHA University, 335 Pangyo, Bundang-gu, Gyeonggi-do, Seongnam-si, 13488, Republic of Korea
| | - Chan Rim
- Department of Pharmacology, Research Institute for Basic Medical Science, School of Medicine, CHA BIO COMPLEX, CHA University, 335 Pangyo, Bundang-gu, Gyeonggi-do, Seongnam-si, 13488, Republic of Korea
| | - Hui-Ju Kim
- Department of Pharmacology, Research Institute for Basic Medical Science, School of Medicine, CHA BIO COMPLEX, CHA University, 335 Pangyo, Bundang-gu, Gyeonggi-do, Seongnam-si, 13488, Republic of Korea
| | - Min-Soo Kwon
- Department of Pharmacology, Research Institute for Basic Medical Science, School of Medicine, CHA BIO COMPLEX, CHA University, 335 Pangyo, Bundang-gu, Gyeonggi-do, Seongnam-si, 13488, Republic of Korea.
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24
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Weder B, Schefer F, van Haaften WT, Patsenker E, Stickel F, Mueller S, Hutter S, Schuler C, Baebler K, Wang Y, Mamie C, Dijkstra G, de Vallière C, Imenez Silva PH, Wagner CA, Frey-Wagner I, Ruiz PA, Seuwen K, Rogler G, Hausmann M. New Therapeutic Approach for Intestinal Fibrosis Through Inhibition of pH-Sensing Receptor GPR4. Inflamm Bowel Dis 2022; 28:109-125. [PMID: 34320209 DOI: 10.1093/ibd/izab140] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Patients suffering from inflammatory bowel diseases (IBDs) express increased mucosal levels of pH-sensing receptors compared with non-IBD controls. Acidification leads to angiogenesis and extracellular matrix remodeling. We aimed to determine the expression of pH-sensing G protein-coupled receptor 4 (GPR4) in fibrotic lesions in Crohn's disease (CD) patients. We further evaluated the effect of deficiency in Gpr4 or its pharmacologic inhibition. METHODS Paired samples from fibrotic and nonfibrotic terminal ileum were obtained from CD patients undergoing ileocaecal resection. The effects of Gpr4 deficiency were assessed in the spontaneous Il-10-/- and the chronic dextran sodium sulfate (DSS) murine colitis model. The effects of Gpr4 deficiency and a GPR4 antagonist (39c) were assessed in the heterotopic intestinal transplantation model. RESULTS In human terminal ileum, increased expression of fibrosis markers was accompanied by an increase in GPR4 expression. A positive correlation between the expression of procollagens and GPR4 was observed. In murine disease models, Gpr4 deficiency was associated with a decrease in angiogenesis and fibrogenesis evidenced by decreased vessel length and expression of Edn, Vegfα, and procollagens. The heterotopic animal model for intestinal fibrosis, transplanted with terminal ileum from Gpr4-/- mice, revealed a decrease in mRNA expression of fibrosis markers and a decrease in collagen content and layer thickness compared with grafts from wild type mice. The GPR4 antagonist decreased collagen deposition. The GPR4 expression was also observed in human and murine intestinal fibroblasts. The GPR4 inhibition reduced markers of fibroblast activation stimulated by low pH, notably Acta2 and cTgf. CONCLUSIONS Expression of GPR4 positively correlates with the expression of profibrotic genes and collagen. Deficiency of Gpr4 is associated with a decrease in angiogenesis and fibrogenesis. The GPR4 antagonist decreases collagen deposition. Targeting GPR4 with specific inhibitors may constitute a new treatment option for IBD-associated fibrosis.
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Affiliation(s)
- Bruce Weder
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Fabian Schefer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Wouter Tobias van Haaften
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.,Department of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands
| | - Eleonora Patsenker
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Sebastian Mueller
- Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany
| | - Senta Hutter
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Cordelia Schuler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Katharina Baebler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Yu Wang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Céline Mamie
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Pedro H Imenez Silva
- Institute of Physiology, University of Zurich, Zurich, Switzerland and National Center of Competence in Research Kidney Control of Homeostasis, Switzerland
| | - Carsten A Wagner
- Institute of Physiology, University of Zurich, Zurich, Switzerland and National Center of Competence in Research Kidney Control of Homeostasis, Switzerland
| | - Isabelle Frey-Wagner
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Klaus Seuwen
- Novartis Institutes for Biomedical Research, Forum1 Novartis Campus, Basel, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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25
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GPR65 (TDAG8) inhibits intestinal inflammation and colitis-associated colorectal cancer development in experimental mouse models. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166288. [PMID: 34628032 PMCID: PMC8629932 DOI: 10.1016/j.bbadis.2021.166288] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 10/03/2021] [Accepted: 10/05/2021] [Indexed: 02/06/2023]
Abstract
GPR65 (TDAG8) is a proton-sensing G protein-coupled receptor predominantly expressed in immune cells. Genome-wide association studies (GWAS) have identified GPR65 gene polymorphisms as an emerging risk factor for the development of inflammatory bowel disease (IBD). Patients with IBD have an elevated risk of developing colorectal cancer when compared to the general population. To study the role of GPR65 in intestinal inflammation and colitis-associated colorectal cancer (CAC), colitis and CAC were induced in GPR65 knockout (KO) and wild-type (WT) mice using dextran sulfate sodium (DSS) and azoxymethane (AOM)/DSS, respectively. Disease severity parameters such as fecal score, colon shortening, histopathology, and mesenteric lymph node enlargement were aggravated in GPR65 KO mice compared to WT mice treated with DSS. Elevated leukocyte infiltration and fibrosis were observed in the inflamed colon of GPR65 KO when compared to WT mice which may represent a cellular mechanism for the observed exacerbation of intestinal inflammation. In line with high expression of GPR65 in infiltrated leukocytes, GPR65 gene expression was increased in inflamed intestinal tissue samples of IBD patients compared to normal intestinal tissues. Moreover, colitis-associated colorectal cancer development was higher in GPR65 KO mice than WT mice when treated with AOM/DSS. Altogether, our data demonstrate that GPR65 suppresses intestinal inflammation and colitis-associated tumor development in murine colitis and CAC models, suggesting potentiation of GPR65 with agonists may have an anti-inflammatory therapeutic effect in IBD and reduce the risk of developing colitis-associated colorectal cancer.
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26
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Comes N, Gasull X, Callejo G. Proton Sensing on the Ocular Surface: Implications in Eye Pain. Front Pharmacol 2021; 12:773871. [PMID: 34899333 PMCID: PMC8652213 DOI: 10.3389/fphar.2021.773871] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 11/09/2021] [Indexed: 01/15/2023] Open
Abstract
Protons reaching the eyeball from exogenous acidic substances or released from damaged cells during inflammation, immune cells, after tissue injury or during chronic ophthalmic conditions, activate or modulate ion channels present in sensory nerve fibers that innervate the ocular anterior surface. Their identification as well as their role during disease is critical for the understanding of sensory ocular pathophysiology. They are likely to mediate some of the discomfort sensations accompanying several ophthalmic formulations and may represent novel targets for the development of new therapeutics for ocular pathologies. Among the ion channels expressed in trigeminal nociceptors innervating the anterior surface of the eye (cornea and conjunctiva) and annex ocular structures (eyelids), members of the TRP and ASIC families play a critical role in ocular acidic pain. Low pH (pH 6) activates TRPV1, a polymodal ion channel also activated by heat, capsaicin and hyperosmolar conditions. ASIC1, ASIC3 and heteromeric ASIC1/ASIC3 channels present in ocular nerve terminals are activated at pH 7.2–6.5, inducing pain by moderate acidifications of the ocular surface. These channels, together with TRPA1, are involved in acute ocular pain, as well as in painful sensations during allergic keratoconjunctivitis or other ophthalmic conditions, as blocking or reducing channel expression ameliorates ocular pain. TRPV1, TRPA1 and other ion channels are also present in corneal and conjunctival cells, promoting inflammation of the ocular surface after injury. In addition to the above-mentioned ion channels, members of the K2P and P2X ion channel families are also expressed in trigeminal neurons, however, their role in ocular pain remains unclear to date. In this report, these and other ion channels and receptors involved in acid sensing during ocular pathologies and pain are reviewed.
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Affiliation(s)
- Núria Comes
- Neurophysiology Laboratory, Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Xavier Gasull
- Neurophysiology Laboratory, Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Gerard Callejo
- Neurophysiology Laboratory, Department of Biomedicine, Medical School, Institute of Neurosciences, Universitat de Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
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27
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de Vallière C, Bäbler K, Busenhart P, Schwarzfischer M, Maeyashiki C, Schuler C, Atrott K, Lang S, Spalinger MR, Scharl M, Ruiz-Castro PA, Hausmann M, Rogler G. A Novel OGR1 (GPR68) Inhibitor Attenuates Inflammation in Murine Models of Colitis. Inflamm Intest Dis 2021; 6:140-153. [PMID: 34722644 DOI: 10.1159/000517474] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/13/2021] [Indexed: 01/17/2023] Open
Abstract
Background and Aims Local extracellular acidification is associated with several conditions, such as ischemia, cancer, metabolic disease, respiratory diseases, and inflammatory bowel disease (IBD). Several recent studies reported a link between IBD and a family of pH-sensing G protein-coupled receptors. Our previous studies point to an essential role for OGR1 (GPR68) in the modulation of intestinal inflammation and fibrosis. In the current study, we evaluated the effects of a novel OGR1 inhibitor in murine models of colitis. Methods The effects of a novel small-molecule OGR1 inhibitor were assessed in the acute and chronic dextran sulfate sodium (DSS) murine models of colitis. Macroscopic disease indicators of intestinal inflammation were evaluated, and epithelial damage and immune cell infiltration and proliferation were assessed by immunohistochemistry. Results The OGR1 inhibitor ameliorated clinical parameters in acute and chronic DSS-induced colitis. In mice treated with the OGR1 inhibitor, endoscopy showed no thickening and normal vascularity, while fibrin was not detected. Histopathological findings revealed a decrease in severity of colonic inflammation in the OGR1 inhibitor group when compared to vehicle-DSS controls. In OGR1 inhibitor-treated mice, staining for the macrophage marker F4/80 and cellular proliferation marker Ki-67 revealed a reduction of infiltrating macrophages and slightly enhanced cell proliferation, respectively. This was accompanied by a reduction in pro-inflammatory cytokines, TNF and IL-6, and the fibrosis marker TGF-β1. Conclusion This is the first report providing evidence that a pharmacological inhibition of OGR1 has a therapeutic effect in murine colitis models. Our data suggest that targeting proton-sensing OGR1 using specific small-molecule inhibitors may be a novel therapeutic approach for the treatment of IBD.
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Affiliation(s)
- Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Katharina Bäbler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Philipp Busenhart
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Marlene Schwarzfischer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Cordelia Schuler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Kirstin Atrott
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Silvia Lang
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Marianne R Spalinger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, Zurich, Switzerland
| | - Pedro A Ruiz-Castro
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, (USZ), University of Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, Zurich, Switzerland
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28
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Tabasi F, Hasanpour V, Sarhadi S, Kaykhaei MA, Pourzand P, Heravi M, Langari AA, Bahari G, Taheri M, Hashemi M, Ghavami S. Association of miR-499 Polymorphism and Its Regulatory Networks with Hashimoto Thyroiditis Susceptibility: A Population-Based Case-Control Study. Int J Mol Sci 2021; 22:10094. [PMID: 34576267 PMCID: PMC8470033 DOI: 10.3390/ijms221810094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 12/29/2022] Open
Abstract
Hashimoto thyroiditis (HT) is a common autoimmune disorder with a strong genetic background. Several genetic factors have been suggested, yet numerous genetic contributors remain to be fully understood in HT pathogenesis. MicroRNAs (miRs) are gene expression regulators critically involved in biological processes, of which polymorphisms can alter their function, leading to pathologic conditions, including autoimmune diseases. We examined whether miR-499 rs3746444 polymorphism is associated with susceptibility to HT in an Iranian subpopulation. Furthermore, we investigated the potential interacting regulatory network of the miR-499. This case-control study included 150 HT patients and 152 healthy subjects. Genotyping of rs3746444 was performed by the PCR-RFLP method. Also, target genomic sites of the polymorphism were predicted using bioinformatics. Our results showed that miR-499 rs3746444 was positively associated with HT risk in heterozygous (OR = 3.32, 95%CI = 2.00-5.53, p < 0.001, CT vs. TT), homozygous (OR = 2.81, 95%CI = 1.30-6.10, p = 0.014, CC vs. TT), dominant (OR = 3.22, 95%CI = 1.97-5.25, p < 0.001, CT + CC vs. TT), overdominant (OR = 2.57, 95%CI = 1.62-4.09, p < 0.001, CC + TT vs. CT), and allelic (OR = 1.92, 95%CI = 1.37-2.69, p < 0.001, C vs. T) models. Mapping predicted target genes of miR-499 on tissue-specific-, co-expression-, and miR-TF networks indicated that main hub-driver nodes are implicated in regulating immune system functions, including immunorecognition and complement activity. We demonstrated that miR-499 rs3746444 is linked to HT susceptibility in our population. However, predicted regulatory networks revealed that this polymorphism is contributing to the regulation of immune system pathways.
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Affiliation(s)
- Farhad Tabasi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (F.T.); (P.P.); (M.H.); (G.B.)
- Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran 1411713116, Iran
| | - Vahed Hasanpour
- Student Research Committee, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran;
| | - Shamim Sarhadi
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz 5166616471, Iran;
| | - Mahmoud Ali Kaykhaei
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (M.A.K.); (M.T.)
- Department of Endocrinology, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
| | - Pouria Pourzand
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (F.T.); (P.P.); (M.H.); (G.B.)
| | - Mehrdad Heravi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (F.T.); (P.P.); (M.H.); (G.B.)
| | - Ahmad Alinaghi Langari
- Student Research Committee, School of Medicine, Kerman University of Medical Sciences, Kerman 7616913555, Iran;
| | - Gholamreza Bahari
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (F.T.); (P.P.); (M.H.); (G.B.)
- Children and Adolescent Health Research Center, Resistant Tuberculosis Institute, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran
| | - Mohsen Taheri
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (M.A.K.); (M.T.)
| | - Mohammad Hashemi
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (F.T.); (P.P.); (M.H.); (G.B.)
- Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan 9816743463, Iran; (M.A.K.); (M.T.)
| | - Saeid Ghavami
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine, Katowice School of Technology, 40-555 Katowice, Poland
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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29
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Sisignano M, Fischer MJM, Geisslinger G. Proton-Sensing GPCRs in Health and Disease. Cells 2021; 10:cells10082050. [PMID: 34440817 PMCID: PMC8392051 DOI: 10.3390/cells10082050] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/05/2021] [Accepted: 08/06/2021] [Indexed: 12/17/2022] Open
Abstract
The group of proton-sensing G-protein coupled receptors (GPCRs) consists of the four receptors GPR4, TDAG8 (GPR65), OGR1 (GPR68), and G2A (GPR132). These receptors are cellular sensors of acidification, a property that has been attributed to the presence of crucial histidine residues. However, the pH detection varies considerably among the group of proton-sensing GPCRs and ranges from pH of 5.5 to 7.8. While the proton-sensing GPCRs were initially considered to detect acidic cellular environments in the context of inflammation, recent observations have expanded our knowledge about their physiological and pathophysiological functions and many additional individual and unique features have been discovered that suggest a more differentiated role of these receptors in health and disease. It is known that all four receptors contribute to different aspects of tumor biology, cardiovascular physiology, and asthma. However, apart from their overlapping functions, they seem to have individual properties, and recent publications identify potential roles of individual GPCRs in mechanosensation, intestinal inflammation, oncoimmunological interactions, hematopoiesis, as well as inflammatory and neuropathic pain. Here, we put together the knowledge about the biological functions and structural features of the four proton-sensing GPCRs and discuss the biological role of each of the four receptors individually. We explore all currently known pharmacological modulators of the four receptors and highlight potential use. Finally, we point out knowledge gaps in the biological and pharmacological context of proton-sensing GPCRs that should be addressed by future studies.
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Affiliation(s)
- Marco Sisignano
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany;
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
- Correspondence:
| | - Michael J. M. Fischer
- Center for Physiology and Pharmacology, Institute of Physiology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria;
| | - Gerd Geisslinger
- Institute of Clinical Pharmacology, Pharmazentrum Frankfurt/ZAFES, University Hospital of Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany;
- Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
- Fraunhofer Cluster of Excellence for Immune-Mediated Diseases (CIMD), Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany
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Ion Channels, Transporters, and Sensors Interact with the Acidic Tumor Microenvironment to Modify Cancer Progression. Rev Physiol Biochem Pharmacol 2021; 182:39-84. [PMID: 34291319 DOI: 10.1007/112_2021_63] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Solid tumors, including breast carcinomas, are heterogeneous but typically characterized by elevated cellular turnover and metabolism, diffusion limitations based on the complex tumor architecture, and abnormal intra- and extracellular ion compositions particularly as regards acid-base equivalents. Carcinogenesis-related alterations in expression and function of ion channels and transporters, cellular energy levels, and organellar H+ sequestration further modify the acid-base composition within tumors and influence cancer cell functions, including cell proliferation, migration, and survival. Cancer cells defend their cytosolic pH and HCO3- concentrations better than normal cells when challenged with the marked deviations in extracellular H+, HCO3-, and lactate concentrations typical of the tumor microenvironment. Ionic gradients determine the driving forces for ion transporters and channels and influence the membrane potential. Cancer and stromal cells also sense abnormal ion concentrations via intra- and extracellular receptors that modify cancer progression and prognosis. With emphasis on breast cancer, the current review first addresses the altered ion composition and the changes in expression and functional activity of ion channels and transporters in solid cancer tissue. It then discusses how ion channels, transporters, and cellular sensors under influence of the acidic tumor microenvironment shape cancer development and progression and affect the potential of cancer therapies.
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31
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Erra Díaz F, Ochoa V, Merlotti A, Dantas E, Mazzitelli I, Gonzalez Polo V, Sabatté J, Amigorena S, Segura E, Geffner J. Extracellular Acidosis and mTOR Inhibition Drive the Differentiation of Human Monocyte-Derived Dendritic Cells. Cell Rep 2021; 31:107613. [PMID: 32375041 DOI: 10.1016/j.celrep.2020.107613] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 01/31/2020] [Accepted: 04/14/2020] [Indexed: 12/13/2022] Open
Abstract
During inflammation, recruited monocytes can differentiate either into macrophages or dendritic cells (DCs); however, little is known about the environmental factors that determine this cell fate decision. Low extracellular pH is a hallmark of a variety of inflammatory processes and solid tumors. Here, we report that low pH dramatically promotes the differentiation of monocytes into DCs (monocyte-derived DCs [mo-DCs]). This process is associated with a reduction in glucose consumption and lactate production, the upregulation of mitochondrial respiratory chain genes, and the inhibition of mTORC1 activity. Interestingly, we also find that both serum starvation and pharmacological inhibition of mTORC1 markedly promote the differentiation of mo-DCs. Our study contributes to better understanding the mechanisms that govern the differentiation of monocytes into DCs and reveals the role of both extracellular pH and mTORC1 as master regulators of monocyte cell fate.
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Affiliation(s)
- Fernando Erra Díaz
- INBIRS, Universidad de Buenos Aires (UBA)-CONICET, Buenos Aires, Argentina
| | - Valeria Ochoa
- INBIRS, Universidad de Buenos Aires (UBA)-CONICET, Buenos Aires, Argentina
| | | | - Ezequiel Dantas
- INBIRS, Universidad de Buenos Aires (UBA)-CONICET, Buenos Aires, Argentina
| | - Ignacio Mazzitelli
- INBIRS, Universidad de Buenos Aires (UBA)-CONICET, Buenos Aires, Argentina
| | | | - Juan Sabatté
- INBIRS, Universidad de Buenos Aires (UBA)-CONICET, Buenos Aires, Argentina
| | | | - Elodie Segura
- Institut Curie, PSL Research University, INSERM, U932 Paris, France
| | - Jorge Geffner
- INBIRS, Universidad de Buenos Aires (UBA)-CONICET, Buenos Aires, Argentina.
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32
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Sayama K, Yuki K, Sugata K, Fukagawa S, Yamamoto T, Ikeda S, Murase T. Carbon dioxide inhibits UVB-induced inflammatory response by activating the proton-sensing receptor, GPR65, in human keratinocytes. Sci Rep 2021; 11:379. [PMID: 33431967 PMCID: PMC7801444 DOI: 10.1038/s41598-020-79519-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/01/2020] [Indexed: 12/13/2022] Open
Abstract
Carbon dioxide (CO2) is the predominant gas molecule emitted during aerobic respiration. Although CO2 can improve blood circulation in the skin via its vasodilatory effects, its effects on skin inflammation remain unclear. The present study aimed to examine the anti-inflammatory effects of CO2 in human keratinocytes and skin. Keratinocytes were cultured under 15% CO2, irradiated with ultraviolet B (UVB), and their inflammatory cytokine production was analyzed. Using multiphoton laser microscopy, the effect of CO2 on pH was observed by loading a three-dimensional (3D)-cultured epidermis with a high-CO2 concentration formulation. Finally, the effect of CO2 on UVB-induced erythema was confirmed. CO2 suppressed the UVB-induced production of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) in keratinocytes and the 3D epidermis. Correcting medium acidification with NaOH inhibited the CO2-induced suppression of TNFα and IL-6 expression in keratinocytes. Moreover, the knockdown of H+-sensing G protein-coupled receptor 65 inhibited the CO2-induced suppression of inflammatory cytokine expression and NF-κB activation and reduced CO2-induced cyclic adenosine monophosphate production. Furthermore, the high-CO2 concentration formulation suppressed UVB-induced erythema in human skin. Hence, CO2 suppresses skin inflammation and can be employed as a potential therapeutic agent in restoring skin immune homeostasis.
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Affiliation(s)
- Keimon Sayama
- Biological Science Research, Kao Corporation, 2606, Akabane, Ichikai-machi, Haga-gun, Tochigi, 321-3497, Japan.,Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Katsuyuki Yuki
- Biological Science Research, Kao Corporation, 2606, Akabane, Ichikai-machi, Haga-gun, Tochigi, 321-3497, Japan
| | - Keiichi Sugata
- Biological Science Research, Kao Corporation, 2606, Akabane, Ichikai-machi, Haga-gun, Tochigi, 321-3497, Japan
| | - Satoko Fukagawa
- Biological Science Research, Kao Corporation, 2606, Akabane, Ichikai-machi, Haga-gun, Tochigi, 321-3497, Japan
| | - Tetsuji Yamamoto
- Biological Science Research, Kao Corporation, 2606, Akabane, Ichikai-machi, Haga-gun, Tochigi, 321-3497, Japan
| | - Shigaku Ikeda
- Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takatoshi Murase
- Biological Science Research, Kao Corporation, 2606, Akabane, Ichikai-machi, Haga-gun, Tochigi, 321-3497, Japan.
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Amini A, Pang D, Hackstein CP, Klenerman P. MAIT Cells in Barrier Tissues: Lessons from Immediate Neighbors. Front Immunol 2020; 11:584521. [PMID: 33329559 PMCID: PMC7734211 DOI: 10.3389/fimmu.2020.584521] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 10/26/2020] [Indexed: 12/12/2022] Open
Abstract
Mucosal-associated invariant T (MAIT) cells are innate-like T cells present at considerable frequencies in human blood and barrier tissues, armed with an expanding array of effector functions in response to homeostatic perturbations. Analogous to other barrier immune cells, their phenotype and function is driven by crosstalk with host and dynamic environmental factors, most pertinently the microbiome. Given their distribution, they must function in diverse extracellular milieus. Tissue-specific and adapted functions of barrier immune cells are shaped by transcriptional programs and regulated through a blend of local cellular, inflammatory, physiological, and metabolic mediators unique to each microenvironment. This review compares the phenotype and function of MAIT cells with other barrier immune cells, highlighting potential areas for future exploration. Appreciation of MAIT cell biology within tissues is crucial to understanding their niche in health and disease.
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Affiliation(s)
- Ali Amini
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - Declan Pang
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - Carl-Philipp Hackstein
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
| | - Paul Klenerman
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
- Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, United Kingdom
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34
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Cerezo M, Rocchi S. Cancer cell metabolic reprogramming: a keystone for the response to immunotherapy. Cell Death Dis 2020; 11:964. [PMID: 33177494 PMCID: PMC7658964 DOI: 10.1038/s41419-020-03175-5] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 12/31/2022]
Abstract
By targeting the tumor microenvironment to stimulate antitumor immunity, immunotherapies have revolutionized cancer treatment. However, many patients do not respond initially or develop secondary resistance. Based on the limited resources in the tumor microenvironment and competition between tumor and immune cells, the field of immune metabolism has produced extensive knowledge showing that targeting metabolism could help to modulate antitumor immunity. However, among all the different potentially targetable metabolic pathways, it remains unclear which have more potential to overcome resistance to immune checkpoint inhibitors. Here, we explore metabolic reprogramming in cancer cells, which might inhibit antitumor immunity, and strategies that can be used to favor the antitumor response.
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Affiliation(s)
- Michaël Cerezo
- INSERM U981, Gustave Roussy, Villejuif, France.
- INSERM U1065, Team 12, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France.
| | - Stéphane Rocchi
- INSERM U1065, Team 12, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France.
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35
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GPR4 Knockout Improves the Neurotoxin-Induced, Caspase-Dependent Mitochondrial Apoptosis of the Dopaminergic Neuronal Cell. Int J Mol Sci 2020; 21:ijms21207517. [PMID: 33053856 PMCID: PMC7589616 DOI: 10.3390/ijms21207517] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/04/2020] [Accepted: 10/08/2020] [Indexed: 12/26/2022] Open
Abstract
In Parkinson’s disease, mitochondrial oxidative stress-mediated apoptosis is a major cause of dopaminergic neuronal loss in the substantia nigra (SN). G protein-coupled receptor 4 (GPR4), previously recognised as an orphan G protein coupled-receptor (GPCR), has recently been claimed as a member of the group of proton-activated GPCRs. Its activity in neuronal apoptosis, however, remains undefined. In this study, we investigated the role of GPR4 in the 1-methyl-4-phenylpyridinium ion (MPP+) and hydrogen peroxide (H2O2)-treated apoptotic cell death of stably GPR4-overexpressing and stably GPR4-knockout human neuroblastoma SH-SY5Y cells. In GPR4-OE cells, MPP+ and H2O2 were found to significantly increase the expression levels of both mRNA and proteins of the pro-apoptotic Bcl-2-associated X protein (Bax) genes, while they decreased the anti-apoptotic B-cell lymphoma 2 (Bcl-2) genes. In addition, MPP+ treatment activated Caspase-3, leading to the cleavage of poly (ADP-ribose) polymerase (PARP) and decreasing the mitochondrial membrane potential (ΔΨm) in GPR4-OE cells. In contrast, H2O2 treatment significantly increased the intracellular calcium ions (Ca2+) and reactive oxygen species (ROS) in GPR4-OE cells. Further, chemical inhibition by NE52-QQ57, a selective antagonist of GPR4, and knockout of GPR4 by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 decreased the Bax/Bcl-2 ratio and ROS generation, and stabilised the ΔΨm, thus protecting the SH-SY5Y cells from MPP+- or H2O2-induced apoptotic cell death. Moreover, the knockout of GPR4 decreased the proteolytic degradation of phosphatidylinositol biphosphate (PIP2) and subsequent release of the endoplasmic reticulum (ER)-stored Ca2+ in the cytosol. Our results suggest that the pharmacological inhibition or genetic deletion of GPR4 improves the neurotoxin-induced caspase-dependent mitochondrial apoptotic pathway, possibly through the modulation of PIP2 degradation-mediated calcium signalling. Therefore, GPR4 presents a potential therapeutic target for neurodegenerative disorders such as Parkinson’s disease.
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36
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Murakami S, Mochimaru Y, Musha S, Kojima R, Deai M, Mogi C, Sato K, Okajima F, Tomura H. Species-Dependent Enhancement of Ovarian Cancer G Protein-Coupled Receptor 1 Activation by Ogerin. Zoolog Sci 2020; 37:103-108. [PMID: 32282140 DOI: 10.2108/zs190106] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 11/17/2019] [Indexed: 11/17/2022]
Abstract
Ogerin is a positive allosteric modulator of human and mouse ovarian cancer G protein-coupled receptors (OGR1s). In the present study, we found that ogerin differentially enhances the activation of OGR1 in various animal species. Amino acid residues of OGR1 that are associated with ogerin are conserved among the species. This suggests that other amino acid residues may be involved in the action of ogerin. Chimeric receptors between human and zebrafish OGR1s showed that the amino acid residues that determine the species specificity of ogerin-induced enhancement reside in the transmembrane and/or intracellular regions of OGR1. This result highlights the importance of first verifying the effectiveness of ogerin to the OGR1 of the species of interest at the cellular level prior to analyzing the physiological and pathophysiological roles of OGR1 in the species.
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Affiliation(s)
- Syo Murakami
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Yuta Mochimaru
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Shiori Musha
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Ryotaro Kojima
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Masahito Deai
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Chihiro Mogi
- Laboratory of Integrated Signaling Systems, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Koichi Sato
- Laboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Fumikazu Okajima
- Laboratory of Pathophysiology, Faculty of Pharmacy, Aomori University, Aomori 030-0943, Japan
| | - Hideaki Tomura
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan, .,Institute of Endocrinology, Meiji University, Kawasaki 214-8571, Japan,
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37
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Wang YB, de Lartigue G, Page AJ. Dissecting the Role of Subtypes of Gastrointestinal Vagal Afferents. Front Physiol 2020; 11:643. [PMID: 32595525 PMCID: PMC7300233 DOI: 10.3389/fphys.2020.00643] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 05/20/2020] [Indexed: 12/22/2022] Open
Abstract
Gastrointestinal (GI) vagal afferents convey sensory signals from the GI tract to the brain. Numerous subtypes of GI vagal afferent have been identified but their individual roles in gut function and feeding regulation are unclear. In the past decade, technical approaches to selectively target vagal afferent subtypes and to assess their function has significantly progressed. This review examines the classification of GI vagal afferent subtypes and discusses the current available techniques to study vagal afferents. Investigating the distribution of GI vagal afferent subtypes and understanding how to access and modulate individual populations are essential to dissect their fundamental roles in the gut-brain axis.
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Affiliation(s)
- Yoko B Wang
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Guillaume de Lartigue
- Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville, FL, United States.,Center for Integrative Cardiovascular and Metabolic Disease, University of Florida, Gainesville, FL, United States
| | - Amanda J Page
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes and Gut Health, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
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38
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Dai SP, Hsieh WS, Chen CH, Lu YH, Huang HS, Chang DM, Huang SL, Sun WH. TDAG8 deficiency reduces satellite glial number and pro-inflammatory macrophage number to relieve rheumatoid arthritis disease severity and chronic pain. J Neuroinflammation 2020; 17:170. [PMID: 32471455 PMCID: PMC7257243 DOI: 10.1186/s12974-020-01851-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 05/21/2020] [Indexed: 11/12/2022] Open
Abstract
Background The autoimmune disease rheumatoid arthritis (RA) affects approximately 1% of the global population. RA is characterized with chronic joint inflammation and often associated with chronic pain. The imbalance of pro-inflammatory and anti-inflammatory macrophages is a feature of RA progression. Glial cells affecting neuronal sensitivity at both peripheral and central levels may also be important for RA progression and associated pain. Genetic variants in the T cell death-associated gene 8 (TDAG8) locus are found to associate with spondyloarthritis. TDAG8 was also found involved in RA disease progression and associated hyperalgesia in the RA mouse model. However, its modulation in RA remains unclear. Methods To address this question, we intra-articularly injected complete Freund’s adjuvant (CFA) into TDAG8+/+, TDAG8−/− or wild-type mice, followed by pain behavioral tests. Joints and dorsal root ganglia were taken, sectioned, and stained with antibodies to observe the number of immune cells, macrophages, and satellite glial cells (SGCs). For compound treatments, compounds were intraperitoneally or orally administered weekly for 9 consecutive weeks after CFA injection. Results We demonstrated that TDAG8 deletion slightly reduced RA pain in the early phase but dramatically attenuated RA progression and pain in the chronic phase (> 7 weeks). TDAG8 deletion inhibited an increase in SGC number and inhibition of SGC function attenuated chronic phase of RA pain, so TDAG8 could regulate SGC number to control chronic pain. TDAG8 deletion also reduced M1 pro-inflammatory macrophage number at 12 weeks, contributing to the attenuation of chronic RA pain. Such results were further confirmed by using salicylanilide derivatives, CCL-2d or LCC-09, to suppress TDAG8 expression and function. Conclusions This study demonstrates that TDAG8 deletion reduced SGC and M1 macrophage number to relieve RA disease severity and associated chronic pain. M1 macrophages are critical for the development and maintenance of RA disease and pain, but glial activation is also required for the chronic phase of RA pain.
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Affiliation(s)
- Shih-Ping Dai
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Wei-Shan Hsieh
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Chien-Hua Chen
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Yueh-Hao Lu
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan
| | - Hsu-Shan Huang
- Graduate Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Der-Ming Chang
- Division of Allergy, Immunology, Rheumatology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shir-Ly Huang
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Hsin Sun
- Department of Life Sciences, National Central University, Jhongli, Taoyuan City, Taiwan. .,Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan.
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39
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Certo M, Marone G, de Paulis A, Mauro C, Pucino V. Lactate: Fueling the fire starter. WILEY INTERDISCIPLINARY REVIEWS. SYSTEMS BIOLOGY AND MEDICINE 2020; 12:e1474. [PMID: 31840439 PMCID: PMC7187281 DOI: 10.1002/wsbm.1474] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/19/2019] [Accepted: 11/25/2019] [Indexed: 02/06/2023]
Abstract
It is becoming increasingly appreciated that intermediates of metabolic pathways, besides their anabolic and catabolic functions, can act as signaling molecules and influence the outcome of immune responses. Although lactate was previously considered as a waste product of glucose metabolism, accumulating evidence has highlighted its pivotal role in regulating diverse biological processes, including immune cell polarization, differentiation and effector functions. In addition, lactate is a key player in modulating tumor immune surveillance. Hence, targeting lactate-induced signaling pathways is a promising tool to reduce inflammation, to prevent autoimmunity and to restore anti-tumor immune response. This article is characterized under: Biological Mechanisms > Metabolism.
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Affiliation(s)
- Michelangelo Certo
- Institute of Inflammation and Ageing, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
| | - Giancarlo Marone
- Department of Public HealthUniversity of Naples Federico IINaplesItaly
- Ospedale dei Colli, Hospital PharmacyNaplesItaly
| | - Amato de Paulis
- Department of Translational Medical Sciences (DISMET)University of Naples Federico IINaplesItaly
- Center for Basic and Clinical Immunology Research (CISI), School of MedicineUniversity of Naples Federico IINaplesItaly
| | - Claudio Mauro
- Institute of Inflammation and Ageing, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
- Institute of Cardiovascular Sciences, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
- Institute of Metabolism and Systems Research, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
| | - Valentina Pucino
- Institute of Inflammation and Ageing, College of Medical and Dental SciencesUniversity of BirminghamBirminghamUK
- Rheumatology Research Group, Institute for Inflammation and Ageing, College of Medical and Dental SciencesQueen Elizabeth Hospital, University of BirminghamBirminghamUK
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40
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Ward C, Meehan J, Gray ME, Murray AF, Argyle DJ, Kunkler IH, Langdon SP. The impact of tumour pH on cancer progression: strategies for clinical intervention. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2020; 1:71-100. [PMID: 36046070 PMCID: PMC9400736 DOI: 10.37349/etat.2020.00005] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Accepted: 02/05/2020] [Indexed: 02/06/2023] Open
Abstract
Dysregulation of cellular pH is frequent in solid tumours and provides potential opportunities for therapeutic intervention. The acidic microenvironment within a tumour can promote migration, invasion and metastasis of cancer cells through a variety of mechanisms. Pathways associated with the control of intracellular pH that are under consideration for intervention include carbonic anhydrase IX, the monocarboxylate transporters (MCT, MCT1 and MCT4), the vacuolar-type H+-ATPase proton pump, and the sodium-hydrogen exchanger 1. This review will describe progress in the development of inhibitors to these targets.
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Affiliation(s)
- Carol Ward
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - James Meehan
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Mark E Gray
- Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG Midlothian, UK
| | - Alan F Murray
- School of Engineering, Institute for Integrated Micro and Nano Systems, EH9 3JL Edinburgh, UK
| | - David J Argyle
- Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Easter Bush, EH25 9RG Midlothian, UK
| | - Ian H Kunkler
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
| | - Simon P Langdon
- Cancer Research UK Edinburgh Centre and Edinburgh Pathology, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, EH4 2XU Edinburgh, UK
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41
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Zeng Z, Mukherjee A, Varghese AP, Yang XL, Chen S, Zhang H. Roles of G protein-coupled receptors in inflammatory bowel disease. World J Gastroenterol 2020; 26:1242-1261. [PMID: 32256014 PMCID: PMC7109274 DOI: 10.3748/wjg.v26.i12.1242] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 01/18/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a complex disease with multiple pathogenic factors. Although the pathogenesis of IBD is still unclear, a current hypothesis suggests that genetic susceptibility, environmental factors, a dysfunctional immune system, the microbiome, and the interactions of these factors substantially contribute to the occurrence and development of IBD. Although existing and emerging drugs have been proven to be effective in treating IBD, none can cure IBD permanently. G protein-coupled receptors (GPCRs) are critical signaling molecules implicated in the immune response, cell proliferation, inflammation regulation and intestinal barrier maintenance. Breakthroughs in the understanding of the structures and functions of GPCRs have provided a driving force for exploring the roles of GPCRs in the pathogenesis of diseases, thereby leading to the development of GPCR-targeted medication. To date, a number of GPCRs have been shown to be associated with IBD, significantly advancing the drug discovery process for IBD. The associations between GPCRs and disease activity, disease severity, and disease phenotypes have also paved new avenues for the precise management of patients with IBD. In this review, we mainly focus on the roles of the most studied proton-sensing GPCRs, cannabinoid receptors, and estrogen-related GPCRs in the pathogenesis of IBD and their potential clinical values in IBD and some other diseases.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Arjudeb Mukherjee
- West China School of Medicine, Sichuan University, Chengdu 410061, Sichuan Province, China
| | | | - Xiao-Li Yang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Sha Chen
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
| | - Hu Zhang
- Department of Gastroenterology, Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 410061, Sichuan Province, China
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42
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Alvarez F, Al-Aubodah TA, Yang YH, Piccirillo CA. Mechanisms of T REG cell adaptation to inflammation. J Leukoc Biol 2020; 108:559-571. [PMID: 32202345 DOI: 10.1002/jlb.1mr0120-196r] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 01/19/2020] [Accepted: 02/03/2020] [Indexed: 12/17/2022] Open
Abstract
Inflammation is an important defense mechanism. In this complex and dynamic process, drastic changes in the tissue micro-environment play key roles in dictating the nature of the evolving immune response. However, uncontrolled inflammation is detrimental, leading to unwanted cellular damage, loss of physiological functions, and even death. As such, the immune system possesses tools to limit inflammation while ensuring rapid and effective clearance of the inflammatory trigger. Foxp3+ regulatory T (TREG ) cells, a potently immunosuppressive CD4+ T cell subset, play a crucial role in immune tolerance by controlling the extent of the response to self and non-self Ags, all-the-while promoting a quick return to immune homeostasis. TREG cells adapt to changes in the local micro-environment enabling them to migrate, proliferate, survive, differentiate, and tailor their suppressive ability at inflamed sites. Several inflammation-associated factors can impact TREG cell functional adaptation in situ including locally released alarmins, oxygen availability, tissue acidity and osmolarity and nutrient availability. Here, we review some of these key signals and pathways that control the adaptation of TREG cell function in inflammatory settings.
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Affiliation(s)
- Fernando Alvarez
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.,Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada
| | - Tho-Alfakar Al-Aubodah
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.,Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada
| | - Yujian H Yang
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.,Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, Québec, Canada.,Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of the McGill University Health Centre, Montréal, Québec, Canada.,Centre of Excellence in Translational Immunology (CETI), Montréal, Québec, Canada.,Division of Experimental Medicine, Department of Medicine, McGill University, Montréal, Québec, Canada
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Abstract
Skeletal involvement is a frequent and troublesome complication in advanced cancers. In the process of tumor cells homing to the skeleton to form bone metastases (BM), different mechanisms allow tumor cells to interact with cells of the bone microenvironment and seed in the bone tissue. Among these, tumor acidosis has been directly associated with tumor invasion and aggressiveness in several types of cancer although it has been less explored in the context of BM. In bone, the association of local acidosis and cancer invasiveness is even more important for tumor expansion since the extracellular matrix is formed by both organic and hard inorganic matrices and bone cells are used to sense protons and adapt or react to a low pH to maintain tissue homeostasis. In the BM microenvironment, increased concentration of protons may derive not only from glycolytic tumor cells but also from tumor-induced osteoclasts, the bone-resorbing cells, and may influence the progression or symptoms of BM in many different ways, by directly enhancing cancer cell motility and aggressiveness, or by modulating the functions of bone cells versus a pro-tumorigenic phenotype, or by inducing bone pain. In this review, we will describe and discuss the cause of acidosis in BM, its role in BM microenvironment, and which are the final effectors that may be targeted to treat metastatic patients.
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Affiliation(s)
- Sofia Avnet
- Orthopaedic Pathophysiology and Regenerative Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
| | - Gemma Di Pompo
- Orthopaedic Pathophysiology and Regenerative Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Silvia Lemma
- Orthopaedic Pathophysiology and Regenerative Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Nicola Baldini
- Orthopaedic Pathophysiology and Regenerative Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
- Department of Biomedical and Neuromotor Sciences, University of Bologna, 40123, Bologna, Italy
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Maeyashiki C, Melhem H, Hering L, Baebler K, Cosin-Roger J, Schefer F, Weder B, Hausmann M, Scharl M, Rogler G, de Vallière C, Ruiz PA. Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model. Sci Rep 2020; 10:1438. [PMID: 31996710 PMCID: PMC6989664 DOI: 10.1038/s41598-020-57657-9] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 12/31/2019] [Indexed: 12/15/2022] Open
Abstract
Proton-sensing ovarian cancer G-protein coupled receptor (OGR1) plays an important role in pH homeostasis. Acidosis occurs at sites of intestinal inflammation and can induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), an evolutionary mechanism that enables cells to cope with stressful conditions. ER stress activates autophagy, and both play important roles in gut homeostasis and contribute to the pathogenesis of inflammatory bowel disease (IBD). Using a human intestinal epithelial cell model, we investigated whether our previously observed protective effects of OGR1 deficiency in experimental colitis are associated with a differential regulation of ER stress, the UPR and autophagy. Caco-2 cells stably overexpressing OGR1 were subjected to an acidic pH shift. pH-dependent OGR1-mediated signalling led to a significant upregulation in the ER stress markers, binding immunoglobulin protein (BiP) and phospho-inositol required 1α (IRE1α), which was reversed by a novel OGR1 inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor. Proton-activated OGR1-mediated signalling failed to induce apoptosis, but triggered accumulation of total microtubule-associated protein 1 A/1B-light chain 3, suggesting blockage of late stage autophagy. Our results show novel functions for OGR1 in the regulation of ER stress through the IRE1α-JNK signalling pathway, as well as blockage of autophagosomal degradation. OGR1 inhibition might represent a novel therapeutic approach in IBD.
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Affiliation(s)
- Chiaki Maeyashiki
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Hassan Melhem
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Larissa Hering
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Katharina Baebler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Jesus Cosin-Roger
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Fabian Schefer
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Bruce Weder
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Martin Hausmann
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, Zurich, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.,Zurich Center for Integrative Human Physiology, Zurich, Switzerland
| | - Cheryl de Vallière
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
| | - Pedro A Ruiz
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
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McMurray KMJ, Vollmer LL, Ahlbrand R, Thomas J, Winter A, Lewkowich IP, Sah R. Immunomodulatory T cell death associated gene-8 (TDAG8) receptor in depression-associated behaviors. Physiol Behav 2019; 209:112598. [PMID: 31271833 DOI: 10.1016/j.physbeh.2019.112598] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 06/26/2019] [Accepted: 06/29/2019] [Indexed: 12/27/2022]
Abstract
Converging evidence supports neuroimmune factors in depression psychopathology. We previously reported reduced depression-like behavior in immunomodulatory G-protein-coupled receptor, T cell death-associated gene-8 (TDAG8) deficient mice. Here, we expand on those findings by investigating depression- and anxiety-associated behaviors, and cytokine profiles in TDAG8-deficient mice. TDAG8-deficiency reduced depression- and anxiety-associated behaviors in the forced swim test (FST), open-field test and elevated zero maze. Interestingly, cytokine expression, particularly IL-6, was attenuated within hippocampus and spleen in TDAG8-deficient mice following the FST. There were no differences in immune-cell frequencies. Collectively, these data suggest a contributory role of TDAG8 in neuroimmune regulation and depression-associated physiology.
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Affiliation(s)
- Katherine M J McMurray
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Lauren Larke Vollmer
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rebecca Ahlbrand
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Joshua Thomas
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Andrew Winter
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Neuroscience Graduate Program, University of Cincinnati, Medical Sciences Building, Room 1058B, 231 Albert Sabin Way, Cincinnati, OH 45237, USA
| | - Ian P Lewkowich
- Division of Immunobiology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA
| | - Renu Sah
- Department of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Neuroscience Graduate Program, University of Cincinnati, Medical Sciences Building, Room 1058B, 231 Albert Sabin Way, Cincinnati, OH 45237, USA; VA Medical Center, Cincinnati, OH 45237, USA
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Kojima R, Horiguchi K, Mochimaru Y, Musha S, Murakami S, Deai M, Mogi C, Sato K, Okajima F, Tomura H. Characterization of molecular mechanisms of extracellular acidification-induced intracellular Ca 2+ increase in LβT2 cells. Biochem Biophys Res Commun 2019; 517:636-641. [PMID: 31400852 DOI: 10.1016/j.bbrc.2019.07.083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Accepted: 07/22/2019] [Indexed: 12/30/2022]
Abstract
Extracellular acidification regulates endocrine cell functions. Ovarian cancer G protein-coupled receptor 1 (OGR1), also known as GPR68, is a proton-sensing G protein-coupled receptor and is activated by extracellular acidification, resulting in the activation of multiple intracellular signaling pathways. In the present study, we found that OGR1 was expressed in some gonadotropic cells in rat anterior pituitary and in LβΤ2 cells, which are used as a model of gonadotropic cells. When we reduced extracellular pH, a transient intracellular Ca2+ increase was detected in LβT2 cells. The Ca2+ increase was inhibited by a Gq/11 inhibitor and Cu2+, which is known as an OGR1 antagonist. We also found that extracellular acidification enhanced GnRH-induced Gaussia luciferase secretion from LβT2 cells. These results suggest that OGR1 may play a role in the regulation of gonadotropic cell function such as its hormone secretion.
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Affiliation(s)
- Ryotaro Kojima
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Kotaro Horiguchi
- Laboratory of Anatomy and Cell Biology, Department of Health Sciences, Kyorin University, Tokyo, 192-8503, Japan
| | - Yuta Mochimaru
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Shiori Musha
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Syo Murakami
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Masahito Deai
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan
| | - Chihiro Mogi
- Laboratory of Integrated Signaling Systems, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512, Japan
| | - Koichi Sato
- Laboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512, Japan
| | - Fumikazu Okajima
- Laboratory of Pathophysiology, Faculty of Pharmacy, Aomori University, Aomori, 030-0943, Japan
| | - Hideaki Tomura
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki, 214-8571, Japan; Institute of Endocrinology, Meiji University, Kawasaki, 214-8571, Japan.
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Musha S, Nagayama S, Murakami S, Kojima R, Deai M, Sato K, Okajima F, Ueharu H, Tomura H. Protons Differentially Activate TDAG8 Homologs from Various Species. Zoolog Sci 2019; 36:105-111. [PMID: 31120644 DOI: 10.2108/zs180128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 10/10/2018] [Indexed: 11/17/2022]
Abstract
Mammalian T cell death-associated gene 8 (TDAG8)s are activated by extracellular protons. In the present study, we examined whether the TDAG8 homologs of other species are activated by protons as they are in mammals. We found that Xenopus TDAG8 also stimulated cAMP response element (CRE)-driven promoter activities reflecting the activation of Gs/cAMP signaling pathways when they are stimulated by protons. On the other hand, the activities of chicken and zebrafish TDAG8s are hardly affected by protons. Results using chimeric receptors of human and zebrafish TDAG8s indicate that the specificity of the proton-induced activation lies in the extracellular region. These results suggest that protons are not an evolutionarily conserved agonist of TDAG8.
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Affiliation(s)
- Shiori Musha
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Suminori Nagayama
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Syo Murakami
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Ryotaro Kojima
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Masahito Deai
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Koichi Sato
- Laboratory of Medical Neuroscience, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan
| | - Fumikazu Okajima
- Laboratory of Pathophysiology, Faculty of Pharmacy, Aomori University, Aomori 030-0943, Japan
| | - Hiroki Ueharu
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan
| | - Hideaki Tomura
- Laboratory of Cell Signaling Regulation, Department of Life Sciences, School of Agriculture, Meiji University, Kawasaki 214-8571, Japan.,Institute of Endocrinology, Meiji University, Kawasaki 214-8571, Japan,
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Metabolite-Sensing G Protein-Coupled Receptors Connect the Diet-Microbiota-Metabolites Axis to Inflammatory Bowel Disease. Cells 2019; 8:cells8050450. [PMID: 31091682 PMCID: PMC6562883 DOI: 10.3390/cells8050450] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/08/2019] [Accepted: 05/09/2019] [Indexed: 02/06/2023] Open
Abstract
Increasing evidence has indicated that diet and metabolites, including bacteria- and host-derived metabolites, orchestrate host pathophysiology by regulating metabolism, immune system and inflammation. Indeed, autoimmune diseases such as inflammatory bowel disease (IBD) are associated with the modulation of host response to diets. One crucial mechanism by which the microbiota affects the host is signaling through G protein-coupled receptors (GPCRs) termed metabolite-sensing GPCRs. In the gut, both immune and nonimmune cells express GPCRs and their activation generally provide anti-inflammatory signals through regulation of both the immune system functions and the epithelial integrity. Members of GPCR family serve as a link between microbiota, immune system and intestinal epithelium by which all these components crucially participate to maintain the gut homeostasis. Conversely, impaired GPCR signaling is associated with IBD and other diseases, including hepatic steatosis, diabetes, cardiovascular disease, and asthma. In this review, we first outline the signaling, function, expression and the physiological role of several groups of metabolite-sensing GPCRs. We then discuss recent findings on their role in the regulation of the inflammation, their existing endogenous and synthetic ligands and innovative approaches to therapeutically target inflammatory bowel disease.
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Pharmacological inhibition of GPR4 remediates intestinal inflammation in a mouse colitis model. Eur J Pharmacol 2019; 852:218-230. [PMID: 30930250 DOI: 10.1016/j.ejphar.2019.03.038] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 03/18/2019] [Accepted: 03/22/2019] [Indexed: 12/31/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by chronic, recurring inflammation of the digestive tract. Current therapeutic approaches are limited and include biologics and steroids such as anti-TNFα monoclonal antibodies and corticosteroids, respectively. Significant adverse drug effects can occur for chronic usage and include increased risk of infection in some patients. GPR4, a pH-sensing G protein-coupled receptor, has recently emerged as a potential therapeutic target for intestinal inflammation. We have assessed the effects of a GPR4 antagonist, 2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole (GPR4 antagonist 13, also known as NE-52-QQ57) in the dextran sulfate sodium (DSS)-induced acute colitis mouse model. The GPR4 antagonist 13 inhibited intestinal inflammation. The clinical parameters such as body weight loss and fecal score were reduced in the GPR4 antagonist 13 treatment group compared to vehicle control. Macroscopic disease indicators such as colon shortening, splenic expansion, and mesenteric lymph node enlargement were all reduced in severity in the GPR4 antagonist 13 treated mice. Histopathological features of active colitis were alleviated in GPR4 antagonist 13 treatment groups compared to vehicle control. Finally, inflammatory gene expression in the colon tissues and vascular adhesion molecule expression in the intestinal endothelia were attenuated by GPR4 antagonist 13. Our results indicate that GPR4 antagonist 13 provides a protective effect in the DSS-induced acute colitis mouse model, and inhibition of GPR4 can be explored as a novel anti-inflammatory approach.
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Alavi MS, Karimi G, Roohbakhsh A. The role of orphan G protein-coupled receptors in the pathophysiology of multiple sclerosis: A review. Life Sci 2019; 224:33-40. [PMID: 30904492 DOI: 10.1016/j.lfs.2019.03.045] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 03/15/2019] [Accepted: 03/19/2019] [Indexed: 01/19/2023]
Abstract
G protein-coupled receptors (GPCRs) are a large family of transmembrane proteins that are expressed in many organs and serve as important drug targets. A new subgroup, namely orphan GPCRs, comprising many of these receptors has been discovered. These receptors exhibit diverse physiological functions and have been considered in many neurological disorders including Alzheimer's disease, Parkinson's disease, and multiple sclerosis (MS). GPR17, GPR30, GPR37, GPR40, GPR50, GPR54, GPR56, GPR65, GPR68, GPR75, GPR84, GPR97, GPR109, GPR124, and GPR126 are orphan GPCRs that have been reported with considerable effects in the prevention and/or treatment of MS in preclinical studies. In the present article, we reviewed the most recent findings regarding the role of orphan GPCRs in the treatment of MS.
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Affiliation(s)
- Mohaddeseh Sadat Alavi
- Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Gholamreza Karimi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Ali Roohbakhsh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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